This invention is directed to substituted azabicyclic compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with proteins that mediate cellular activity.
Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. TNF is released by activated macrophages, activated T-lymphocytes, natural killer cells, mast cells and basophils, fibroblasts, endothelial cells and brain astrocytes among other cells.
The principal in vivo actions of TNF can be broadly classified as inflammatory and catabolic. It has been implicated as a mediator of endotoxic shock, inflammation of joints and of the airways, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. In view of the association of high serum levels of TNF with poor prognosis in sepsis, graft versus host disease and adult respiratory distress syndrome, and its role in many other immunologic processes, this factor is regarded as an important mediator of general inflammation.
TNF primes or activates neutrophils, eosinophils, fibroblasts and endothelial cells to release tissue damaging mediators. TNF also activates monocytes, macrophages and T-lymphocytes to cause the production of colony stimulating factors and other pro-inflammatory cytokines such IL1, IL6, IL8 and GM-CSF, which in some case mediate the end effects of TNF. The ability of TNF to activate T-lymphocytes, monocytes, macrophages and related cells has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection. In order for these cells to become infected with HIV and for HIV replication to take place the cells must be maintained in an activated state. Cytokines such as TNF have been shown to activate HIV replication in monocytes and macrophages. Features of endotoxic shock such as fever, metabolic acidosis, hypotension and intravascular coagulation are thought to be mediated through the actions of TNF on the hypothalamus and in reducing the anti-coagulant activity of vascular endothelial cells. The cachexia associated with certain disease states is mediated through indirect effects on protein catabolism. TNF also promotes bone resorption and acute phase protein synthesis.
The discussion herein relates to disease states associated with TNF including those disease states related to the production of TNF itself, and disease states associated with other cytokines, such as but not limited to IL-1, or IL-6, that are modulated by associated with TNF. For example, a IL-1 associated disease state, where IL-1 production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state associated with TNF. TNF-alpha and TNF-beta are also herein referred to collectively as xe2x80x9cTNFxe2x80x9d unless specifically delineated otherwise, since there is a close structural homology between TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has a capacity to induce similar biological responses and bind to the same cellular receptor.
Cyclic AMP phosphodiesterases are important enzymes which regulate cyclic AMP levels and in turn thereby regulate other important biological reactions. The ability to regulate cyclic AMP phosphodiesterases therefore, has been implicated as being capable of treating assorted biological conditions. In particular, inhibitors of type IV cyclic AMP phosphodiesterase have been implicated as being bronchodilators agents, prophylactic agents useful against asthma and as agents for inhibiting eosinophil accumulation and of the function of eosinophils, and for treating other diseases and conditions characterised by, or having an etiology involving, morbid eosinophil accumulation. Inhibitors of cyclic AMP phosphodiesterase are also implicated in treating inflammatory diseases, proliferative skin diseases and conditions associated with cerebral metabolic inhibition.
It has already been reported that certain substituted monocyclic aromatic compounds have valuable pharmaceutical properties, in particular the ability to regulate proteins that mediate cellular activity, for example, type IV cyclic AMP phosphodiesterase and/or TNF, as described, for example, in the specification of International Patent Application Publication No. WO 95/04045.
Certain substituted bicyclic aromatic compounds, for example amino-substituted benzofurans and benzothiophenes, are reported in European Patent Application EP-A-0685475, to have the ability to regulate elevated cellular cyclic AMP levels probably due to inhibition of type IV cyclic AMP phosphodiesterase.
Further examples of substituted bicyclic aromatic compounds with type IV cyclic AMP phosphodiesterase and/or TNF inhibitory activity include dihydrobenzofurans reported in WO 96/36625 and WO 96/36626.
We have now found a novel group of azabicyclic compounds which have valuable pharmaceutical properties, in particular the ability to regulate proteins that mediate cellular activity, for example, cyclic AMP phosphodiesterases (in particular type IV) and/or TNF.
Thus, in one aspect, the present invention is directed to compounds of general formula (I): 
wherein 
represents a bicyclic ring system, of about 10 to about 13 ring members, in which the ring 
is an azaheterocycle, and the ring 
represents an azaheteroaryl ring, or an optionally halo substituted benzene ring;
R1 represents hydrogen or a straight- or branched-chain alkyl group of 1 to about 4 carbon atoms, optionally substituted by hydroxy or one or more halogen atoms, or when Z1 represents a direct bond R1 may also represent a lower alkenyl or lower alkynyl group, or a formyl group;
R2 represents hydrogen, alkenyl, alkoxy, alkyl, alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl, cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, hydroxy, xe2x80x94SO2NR4R5, xe2x80x94NR4SO2R5, xe2x80x94NR4R5, xe2x80x94C(xe2x95x90O)R5, xe2x80x94C(xe2x95x90O)C(xe2x95x90O)R5, xe2x80x94C(xe2x95x90O)NR4R5, xe2x80x94C(xe2x95x90O)OR5, xe2x80x94O(Cxe2x95x90O)NR4R5, or xe2x80x94NR4C(xe2x95x90O)R5 (where R4 and R5, which may be the same or different, each represent a hydrogen atom, or an alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl group);
R3 represents a group selected from:
xe2x80x94C(xe2x95x90Z)xe2x80x94N(R7)R6xe2x80x83xe2x80x83(i)
xe2x80x94C(xe2x95x90Z)xe2x80x94CHR12R6xe2x80x83xe2x80x83(ii)
xe2x80x94C(xe2x95x90Z)xe2x80x94R6xe2x80x83xe2x80x83(iii)
xe2x80x83xe2x80x94CR8xe2x95x90C(R9)(CH2)pxe2x80x94R6xe2x80x83xe2x80x83(iv)
xe2x80x94C(R10)xe2x95x90C(R11)R12xe2x80x83xe2x80x83(v)
xe2x80x94C(R13)(R10)C(R11)(R14)R12xe2x80x83xe2x80x83(vi)
xe2x80x94C(R8)(R15)CH(R9)(CH2)pxe2x80x94R6xe2x80x83xe2x80x83(vii)
xe2x80x94R6xe2x80x83xe2x80x83(viii)
xe2x80x94N(R16)C(xe2x95x90Z)R6xe2x80x83xe2x80x83(ix)
xe2x80x94C(R17)xe2x95x90Nxe2x80x94OC(xe2x95x90O)R18xe2x80x83xe2x80x83(x)
xe2x80x94C(xe2x95x90O)xe2x80x94N(R19)OR20xe2x80x83xe2x80x83(xi)
xe2x80x94Cxe2x89xa1Cxe2x80x94R6xe2x80x83xe2x80x83(xii)
xe2x80x94CH2xe2x80x94C(xe2x95x90Z)xe2x80x94R6xe2x80x83xe2x80x83(xiii)
xe2x80x94C(xe2x95x90Z)xe2x80x94C(xe2x95x90Z)R6xe2x80x83xe2x80x83(xiv)
xe2x80x94CH2xe2x80x94NHR6xe2x80x83xe2x80x83(xv)
xe2x80x94CH2xe2x80x94ZR6xe2x80x83xe2x80x83(xvi)
xe2x80x94CH2xe2x80x94SOR6xe2x80x83xe2x80x83(xvii)
xe2x80x94CH2xe2x80x94SO2R6xe2x80x83xe2x80x83(xviii)
xe2x80x94CF2xe2x80x94OR6xe2x80x83xe2x80x83(xix)
xe2x80x94NHxe2x80x94CH2R6xe2x80x83xe2x80x83(xx)
xe2x80x94Zxe2x80x94CH2R6xe2x80x83xe2x80x83(xxi)
xe2x80x94SOxe2x80x94CH2R6xe2x80x83xe2x80x83(xxii)
xe2x80x94SO2xe2x80x94CH2R6xe2x80x83xe2x80x83(xxiv)
xe2x80x94Oxe2x80x94CF2R6xe2x80x83xe2x80x83(xxv)
xe2x80x94Oxe2x80x94C(xe2x95x90Z)R6xe2x80x83xe2x80x83(xxiii)
xe2x80x94Nxe2x95x90Nxe2x80x94R6xe2x80x83xe2x80x83(xxvi)
xe2x80x83xe2x80x94NHxe2x80x94SO2R6xe2x80x83xe2x80x83(xxvii)
xe2x80x94SO2xe2x80x94NR21R22xe2x80x83xe2x80x83(xxviii)
xe2x80x94CZxe2x80x94CZxe2x80x94NHR6xe2x80x83xe2x80x83(xxix)
xe2x80x94NHxe2x80x94COxe2x80x94OR6xe2x80x83xe2x80x83(xxx)
xe2x80x94Oxe2x80x94COxe2x80x94NHR6xe2x80x83xe2x80x83(xxxi)
xe2x80x94NHxe2x80x94COxe2x80x94NHR6xe2x80x83xe2x80x83(xxxii)
xe2x80x94R23xe2x80x83xe2x80x83(xxxiii)
xe2x80x94CX1xe2x95x90CX2R6xe2x80x83xe2x80x83(xxxiv)
xe2x80x94C(xe2x95x90NOR24)xe2x80x94CH2)qR6xe2x80x83xe2x80x83(xxxv)
xe2x80x94CH2CONH(CH2)qR6xe2x80x83xe2x80x83(xxxvi)
xe2x80x94CH2xe2x80x94NHCO(CH2)qR6xe2x80x83xe2x80x83(xxxvii)
xe2x80x94CH2xe2x80x94COxe2x80x94CH2R6xe2x80x83xe2x80x83(xxxviii)
xe2x80x94C(xe2x95x90NR25)xe2x80x94NH(CH2)qR6xe2x80x83xe2x80x83(xxxix)
xe2x80x94C(X3)xe2x95x90N(CH2)qR6xe2x80x83xe2x80x83(xxxx)
xe2x80x94CH(X4)xe2x80x94CH2R6 xe2x80x83xe2x80x83(xxxxi)
[where:
R6 is aryl or heteroaryl;
R7 is a hydrogen atom or an alkyl or amino group;
R8 and R9, which may be the same or different, is each a hydrogen atom or alkyl, xe2x80x94CO2R5, xe2x80x94C(xe2x95x90Z)NR26R27 (where R26 and R27 may be the same or different and each is as described for R5), xe2x80x94CN or xe2x80x94CH2CN;
R10 and R11, which may be the same or different, is each a group xe2x80x94CH2)pR6;
R12 is a hydrogen atom or an alkyl group;
R13 is a hydrogen or halogen atom or an xe2x80x94OR28 group (where R28 is a hydrogen atom or an alkyl, alkenyl, alkoxyalkyl, acyl, carboxamido or thiocarboxamido group);
R14 is a hydrogen atom or an alkyl group;
R15 is a hydrogen atom or a hydroxyl group;
R16 is a hydrogen atom or an alkyl, amino, aryl, arylalkyl, or hydroxy group;
R17 is a hydrogen atom or a C1-4alkyl or arylC1-4alkyl group;
R18 is an amino, alkylamino, arylamino, alkoxy or aryloxy group;
R19 is an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group;
R20 is R5, (CH2)pCO2R5 or (CH2)pCOR5;
R21 is a group xe2x80x94L1xe2x80x94R29 [where L1 is a straight or branched C1-6alkylene chain, a straight or branched C2-6alkenylene chain, a straight or branched C2-6alkynylene chain or a straight or branched C1-6alkylene chain containing an oxygen or sulphur atom, a phenylene, imino (xe2x80x94NHxe2x80x94) or alkylimino linkage, or a sulphinyl or sulphonyl group, in which each of the alkylene, alkenylene and alkynylene chains may be optionally substituted, the substituents chosen from alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl or oxo; and R29 is hydrogen, or arylalkoxycarbonyl, carboxy or an acid bioisostere, cyano, xe2x80x94NY1Y2, {where Y1 and Y2 are independently hydrogen, alkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, or the group xe2x80x94NY1Y2 may form a 4-6 membered cyclic amine (which may optionally contain a further heteroatom selected from O, S, or NY1, or which may be fused to an additional aromatic or heteroaromatic ring)}], or R21 is an optionally substituted cycloalkyl, cycloalkenyl or heterocycloalkyl group which may optionally be fused to an additional optionally substituted aromatic, heteroaromatic, carbocyclic or heterocycloalkyl ring (where the one or more optional substituents, for either or both rings, may be represented by xe2x80x94L1xe2x80x94R29);
R22 is a hydrogen atom, a group xe2x80x94L1xe2x80x94R29, or an optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group which may optionally be fused to an additional optionally substituted aromatic, heteroaromatic, carbocyclic or heterocycloalkyl ring (where the one or more optional substituents, for either or both rings, may be represented by xe2x80x94L1xe2x80x94R29); or both R21 and R22 represent aryl or heteroaryl each optionally substituted by xe2x80x94L 1xe2x80x94R29; or the group xe2x80x94NR21R22 represents an optionally substituted saturated or unsaturated 3 to 8 membered cyclic amine ring, which may optionally contain one or more heteroatoms selected from O, S or N, and may also be fused to an additional optionally substituted aromatic, heteroaromatic, carbocyclic or heterocycloalkyl ring (where the one or more optional substituents, for any of the rings, may be represented by xe2x80x94L1xe2x80x94R29); 
{where:
R30 is a hydrogen atom or an alkyl, hydroxyalkyl or alkoxyalkyl group;
R31 is a hydrogen atom or an alkyl, carboxy, CONHOR14, N-alkylaminoalkyl, N,N-dialkylaminoalkyl or alkoxyalkyl group; or R30 and R31 together represent a xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 group;
R32 is a hydrogen atom, or amino, alkyl, aminoalkyl, hydroxyalkyl, hydroxy, acyl, alkoxycarbonyl, methoxycarbonylalkyl, xe2x80x94CH2)pCONY3Y4 (where Y3 and Y4 are each independently hydrogen or alkyl), xe2x80x94CH2)pSO2NY3Y4, xe2x80x94CH2)pPO3H2, xe2x80x94(CH2)pSO2NHCOalkyl, or xe2x80x94CH2)pSO2NHCOR6;
R33 is C1-4alkyl, CH2NHCOCONH2, CHxe2x95x90C(R43)R44 (where R43 is R44 or fluorine and R44 is hydrogen or C1-4alkyl optionally substituted by 1 to 3 fluorine atoms), cyclopropyl (optionally substituted by R43), CN, CH2OR44 or CH2NR44R45 (where
R45 is hydrogen, OR44, or C1-4alkyl optionally substituted by 1 to 3 fluorine atoms, or the group NR44R45 represents a 5 to 7 membered cyclic amine optionally containing one or more additional heteroatom selected from O, N, or S);
R34 is methyl or ethyl optionally substituted by 1 or more halogen atoms;
R35 is R14, xe2x80x94OR14, xe2x80x94CO2R14, xe2x80x94COR14, xe2x80x94CN, xe2x80x94CONY3Y4 or xe2x80x94NY3Y4;
R36 is xe2x80x94C(xe2x95x90Z)R14, xe2x80x94CO2R14, xe2x80x94CONY3Y4 or xe2x80x94CN;
R37 and R39, which may be the same or different, is each a hydrogen atom, alkyl, acyl, arylalkyl, xe2x80x94CH2)pCO2R5, xe2x80x94CONHR5, heteroarylalkyl, aryl, or heteroaryl;
R38 is acyl, aroyl, xe2x80x94C(xe2x95x90O)cycloalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, carboxy, alkoxyalkyl, xe2x80x94NO2, xe2x80x94CH2OH, xe2x80x94CN, xe2x80x94NR14COR5, xe2x80x94NR14CONY5Y6, xe2x80x94NR14SO2R46 [where R46 is alkyl, cycloalkyl, trifluoromethyl, aryl, arylalkyl or xe2x80x94NY5Y6 (where Y5 and Y6 are independently selected from hydrogen, alkyl, cycloalkyl, aryl or arylalkyl, or Y5 and Y6 together form a 4- to 7-membered heterocyclic or carbocyclic ring)], xe2x80x94SO2R46 or xe2x80x94CONY5Y6;
R40 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, acyl, aroyl, xe2x80x94C(xe2x95x90O)cycloalkyl, xe2x80x94CH2OH, alkoxyalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, xe2x80x94CN, xe2x80x94NO2, or xe2x80x94SO2R46;
R41 is xe2x80x94CN, xe2x80x94C(Z)R47 (where R47 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, C1-6alkoxy, arylalkoxy, aryloxy or xe2x80x94NY5Y6) or SO2R46;
R42 is hydrogen, alkyl, cycloalkyl, acyl, aroyl, xe2x80x94C(xe2x95x90O)cycloalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, carboxy, xe2x80x94CN, xe2x80x94SO2R46 or xe2x80x94CONY5Y6;
W is (CH2)r or NR39;
Z3 is an oxygen atom, NR14 or NOR14;
s is zero or an integer 1 to 4;
r is 1 to 4; and
Y is an oxygen atom, C(xe2x95x90O), CH(OH) or C(OR14)(CH2)pR6};
R24 is R5 or CONHR25;
R25 is hydrogen, C1-3alkyl or (CH2)qR6;
p is zero or an integer 1 to 5;
q is zero or 1;
X1 and X2, which may be the same or different, is each a hydrogen or fluorine atom;
X3 is a chlorine or fluorine atom, alkoxy, aryloxy, heteroaryloxy, arylalkyloxy or heteroarylalkyl;
X4 is a halogen atom or hydroxy;
Z represents an, oxygen or sulphur atom];
A1 represents a direct bond, or a straight or branched C1-6alkylene chain optionally substituted by hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl, or A1 represents a straight or branched C2-6alkenylene or C2-6alkynylene chain;
Z1 represents a direct bond, an oxygen or sulphur atom or NH;
n and m each represent zero or 1, provided that n is 1 when m is zero and n is zero when m is 1;
and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (I) and N-oxides thereof, and their prodrugs.
In the present specification, the term xe2x80x9ccompounds of the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the N-oxides, the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits.
Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their N-oxides, salts, and solvates, where the context so permits. For, the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
It is to be understood that R2A1, (R1Z1)n and (R1Z1)m may be attached at either a ring carbon or nitrogen atom whereas R3 is attached at a ring carbon.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as described herein. Preferred acyls contain a C1-4alkyl. Exemplary acyl groups include formyl, acetyl; propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as described herein.
Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Particular alkyl groups have 1 to about 12 carbon atoms in the chain, more particularly from 1 to about 6 carbon atoms. Exemplary alkyl groups for R1 include methyl, fluoromethyl, difluoromethyl, trifluoromethyl and ethyl. Exemplary alkyl groups for R2 include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
xe2x80x9cAlkylsulphonylxe2x80x9d means an alkyl-SO2xe2x80x94 group in which the alkyl group is as previously described. Preferred groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphinylxe2x80x9d means an alkyl-SOxe2x80x94 group in which the alkyl group is as previously described. Preferred groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as described herein. Exemplary groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as previously defined.
xe2x80x9cArylxe2x80x9d as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 10 carbon atoms. When R3 contains an optionally substituted aryl group this may particularly represent an aromatic carbocyclic moiety of about 6 to about 10 carbon atoms such as phenyl or naphthyl optionally substituted with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes, for example, acyl, acylamino, alkyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, aroyl, aroylamino, aryl, arylalkyl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyl, heteroarylamino, heteroaryloxy, hydroxy, hydroxyalkyl, nitro, arylthio, Y7Y8Nxe2x80x94, Y7Y8NCOxe2x80x94 or Y7Y8NSO2xe2x80x94 (where Y7 and Y8 are independently hydrogen, alkyl, aryl, and arylalkyl). Preferred aryl group substituents within R3 include acyl, acylamino, alkoxycarbonyl, alkyl, alkylthio, aroyl, cyano, halo, hydroxy, nitro, Y7Y8Nxe2x80x94, Y7Y8NCOxe2x80x94 and Y7Y8NSO2xe2x80x94 (where Y7 and Y8 are independently hydrogen or alkyl). When R2 contains an optionally substituted aryl group this may particularly represent a phenyl group optionally substituted by one or more substituents selected from the xe2x80x9caryl group substituentsxe2x80x9d listed above. Preferred aryl group substituents within R2 include halogen, alkoxy, carboxamido, cyano and heteroaryl.
xe2x80x9cArylalkylxe2x80x9d means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cArylalkylsulphinylxe2x80x9d means an aryl-alkyl-SOxe2x80x94 group in which the aryl and alkyl moieties are as previously described.
xe2x80x9cArylalkylsulphonylxe2x80x9d means an aryl-alkyl-SOxe2x80x94 group in which the aryl and alkyl moieties are as previously described.
xe2x80x9cArylalkyloxyxe2x80x9d means an arylalkyl-Oxe2x80x94 group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cArylalkyloxycarbonylxe2x80x9d means an arylalkyl-Oxe2x80x94COxe2x80x94 group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cArylalkylthioxe2x80x9d means an arylalkyl-Sxe2x80x94 group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94COxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulphinylxe2x80x9d means an aryl-SOxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylxe2x80x9d means an aryl-SO2xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAzaheterocyclexe2x80x9d means a heterocycle of about 5 to about 7 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, nitrogen and NR5, but excluding compounds where two O or S atoms are in adjacent positions. Exemplary azaheterocycles include pyridyl, imidazolyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, pyridazyl, pyrimidinyl, morpholinyl, piperidinyl.
xe2x80x9cAzaheteroarylxe2x80x9d means an aromatic carbocyclic moiety of 5 or 6 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, or nitrogen. Exemplary azaheteroaryl rings include isoxazolyl, pyridyl and pyrimidinyl.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic monocyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.
xe2x80x9cCycloalkenyloxyxe2x80x9d means a cycloalkenyl-Oxe2x80x94 group in which the cycloalkenyl moiety is as previously defined. Exemplary cycloalkyloxy groups include cyclopentenyloxy, cyclohexenyloxy and cycloheptenyloxy.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
xe2x80x9cCycloalkyloxyxe2x80x9d means a cycloalkyl-Oxe2x80x94 group in which the cycloalkyl moiety is as previously defined. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-COxe2x80x94 group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
xe2x80x9cHeteroarylxe2x80x9d as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur. Examples of suitable optionally substituted heteroaryl groups include furyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazole, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, and 1,2,4-triazinyl groups, optionally substituted by one or more aryl group substituents as defined above. When R2 or R3 contains an optionally substituted heteroaryl group this may particularly represent an optionally substituted xe2x80x9cazaheteroarylxe2x80x9d group. Optional substituents for the heteroaryl group within R2 or R3 include, for example, halogen atoms and alkyl, aryl, arylalkyl, hydroxy, oxo, hydroxyalkyl, haloalkyl (for example trifluoromethyl), alkoxy, haloalkoxy (for example trifluoromethoxy), aryloxy and arylalkyloxy groups. Preferred heteroaryl groups within R2 or R3 include optionally substituted pyridyl. Preferred heteroaryl groups represented by R6 within the groups xe2x80x94C(xe2x95x90Z)NHR6 and xe2x80x94C(xe2x95x90Z)CH2R6 are optionally substituted pyridyl groups, especially wherein the optional substituents are alkyl groups or, more particularly, halogen atoms. Preferred heteroaryl groups represented by R6 within the group xe2x80x94C(xe2x95x90Z)R6 are optionally substituted pyridyl groups, especially wherein the optional substituent is an aryloxy group.
xe2x80x9cHeteroarylalkylxe2x80x9d means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
xe2x80x9cHeteroarylalkoxyxe2x80x9d means an heteroarylalkyl-Oxe2x80x94 group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
xe2x80x9cHeterocycloalkylxe2x80x9d means a cycloalkyl group which contains one or more heteroatoms selected from O, S or NY1.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkyl- group in which alkyl is as previously defined.
Preferred hydroxyalkyl groups contain C1-4alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cY7Y8Nxe2x80x94xe2x80x9d means a substituted or unsubstituted amino group, wherein Y7 and Y8 are as previously described. Exemplary groups include amino (H2Nxe2x80x94), methylamino, ethylmethylamino, dimethylamino and diethylamino.
xe2x80x9cY7Y8NCOxe2x80x94xe2x80x9d means a substituted or unsubstituted carbamoyl group, wherein Y7 and Y8 are as previously described. Exemplary groups are carbamoyl (H2NCOxe2x80x94) and dimethylcarbamoyl (Me2NCOxe2x80x94).
xe2x80x9cY7Y8NSO2xe2x80x94xe2x80x9d means a substituted or unsubstituted sulphamoyl group, wherein Y7 and Y8 are as previously described. Exemplary groups are sulphamoyl (H2NSO2xe2x80x94) and dimethylsulphamoyl (Me2NSO2xe2x80x94).
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof, for example an ester of a compound of formula (I) containing a hydroxy group.
Suitable esters are of many different types, for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
An especially useful class of esters may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates. Additionally, in situations where tautomers of the compounds of formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
With reference to formula (I) above, the following are particular and preferred groupings:
R1 preferably represents a C1-4alkyl group optionally substituted by one or more halogen (e.g. chlorine or fluorine) atoms. R1 more preferably represents methyl or difluoromethyl.
R2 may particularly represent C1-7alkyl (for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl).
R2 may also particularly represent C1-4alkoxy (for example methoxy).
R2 may also particularly represent C3-7cycloalkyl (for example cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl).
R2 may also particularly represent aryl (for example optionally substituted phenyl or naphthyl).
R2 may also particularly represent aryloxy (for example optionally substituted phenoxy).
R2 may also particularly represent heteroaryl (for example optionally substituted thienyl, pyridyl, furanyl).
R2 may also particularly represent heterocycloalkyl (for example tetrahydrofuranyl, tetrahydropyranyl).
R2 may also particularly represent arylalkylsulphonyl (for example 4-methylphenylsulphonyl and 4-methoxyphenylsulphonyl) when the group R2A1xe2x80x94 is attached to a ring nitrogen atom.
It is to be understood that the aforementioned heteroaryl and heterocycloalkyl moieties represented by R2 when containing at least one nitrogen atom may be presented as the corresponding N-oxides.
R3 may particularly represent xe2x80x94OCH2R6, xe2x80x94C(xe2x95x90Z)xe2x80x94N(R7)R6, preferably wherein R7 represents a hydrogen atom, or xe2x80x94C(xe2x95x90Z)xe2x80x94CHR12R6 especially where R12 is hydrogen. Within such groups R6 may preferably represent substituted phenyl, especially a phenyl group substituted on one or both, more preferably on both, of the positions adjacent to a position of attachment of R6 to the rest of the molecule. It is also preferred that the phenyl substituent is alkyl, especially methyl, or halo, especially chloro or fluoro. Within such groups R6 may also preferably represent substituted azaheteroaryl, where the azaheteroaryl group is preferably substituted on one or both, more preferably on both, of the positions adjacent to a position of attachment of R6 to the rest of the molecule. It is also preferred that the heteroaryl substituent is alkyl, especially methyl, or halo, especially chloro or fluoro.
R3 may also particularly represent xe2x80x94C(xe2x95x90Z)xe2x80x94R6 wherein R6 is preferably azaheteroaryl (e.g. pyridyl), particularly when substituted by aryloxy (e.g. 3-chlorophenoxy).
R3 may also particularly represent xe2x80x94CR8xe2x95x90C(R9)(CH2)pxe2x80x94R6 where R8 is preferably CH3 or more preferably hydrogen, R9 is preferably hydrogen, CN or CH3 and p is zero, 1 or 2, especially zero and R6 is as defined above.
R3 may also particularly represent xe2x80x94C(R10)xe2x95x90C(R11)R12 where R10 and R11 are each preferably CH2R6 or especially R6 (where R6 is as defined above), and R12 is hydrogen.
R3 may also particularly represent xe2x80x94C(R13)(R10)C(R11)(R14)R12 where R10 and R11 are each preferably CH2R6 or especially R6 (where R6 is as defined above), R13 is preferably hydrogen or hydroxy, R12 and R14 are preferably methyl or more especially hydrogen.
R3 may also particularly represent xe2x80x94C(R8)(R15)CH(R9)(CH2)pxe2x80x94R6 where R8 is preferably CH3 or more preferably hydrogen, R9 and is preferably hydrogen, CN or CH3, more preferably hydrogen, p is zero, 1 or 2, especially zero, R15 is preferably hydrogen and R6 is as defined above.
R3 may also particularly represent xe2x80x94R6 where R6 is as defined above.
R3 may also particularly represent xe2x80x94N(R16)C(xe2x95x90Z)R6 where R16 is hydrogen and R6 is as defined above.
R3 may also particularly represent xe2x80x94C(R17)xe2x95x90Nxe2x80x94OC(xe2x95x90O)R18 where R17 is C1-4alkyl and R18 is amino.
R3 may also particularly represent xe2x80x94C(xe2x95x90O)xe2x80x94N(R19)OR20 where R19 is C1-4alkyl or aryl and R20 is C1-4alkyl or arylalkyl.
R3 may also particularly represent xe2x80x94Cxe2x89xa1Cxe2x80x94R6, xe2x80x94CH2xe2x80x94NHR6, xe2x80x94CH2xe2x80x94SOR6, xe2x80x94CH2xe2x80x94SO2R6, xe2x80x94CF2xe2x80x94OR6, xe2x80x94NHxe2x80x94CH2R6, xe2x80x94SOxe2x80x94CH2R6, xe2x80x94SO2xe2x80x94CH2R6, xe2x80x94Oxe2x80x94CF2R6, xe2x80x94Nxe2x95x90Nxe2x80x94R6, xe2x80x94NHxe2x80x94SO2R6, xe2x80x94NHxe2x80x94COxe2x80x94OR6, xe2x80x94Oxe2x80x94COxe2x80x94NHR6, xe2x80x94NHxe2x80x94COxe2x80x94NHR6 or xe2x80x94CH2xe2x80x94COxe2x80x94CH2R6 where R6 is as defined above.
R3 may also particularly represent xe2x80x94SO2xe2x80x94NR21 R22 where R21 and R22 are as defined above.
R3 may also particularly represent xe2x80x94CH2xe2x80x94C(xe2x95x90Z)xe2x80x94R6, xe2x80x94C(xe2x95x90Z)xe2x80x94C(xe2x95x90Z)R6, xe2x80x94CH2xe2x80x94ZR6, xe2x80x94Zxe2x80x94CH2R6, CZxe2x80x94CZxe2x80x94NHR6 or xe2x80x94Oxe2x80x94C(xe2x95x90Z)R6 where Z and R6 are as defined above.
R3 may also particularly represent xe2x80x94CX1xe2x95x90CX2R6 where X1, X2 and R6 are as defined above.
R3 may also particularly represent C(xe2x95x90NOR24)(CH2)qR6 where R24, q and R6 are as defined above.
R3 may also particularly represent xe2x80x94CH2xe2x80x94COxe2x80x94NH(CH2)qR6 or xe2x80x94CH2xe2x80x94NHxe2x80x94CO(CH2)qR6 where q and R6 are as defined above.
R3 may also particularly represent xe2x80x94C(xe2x95x90NR25xe2x80x94NH(CH2)qR6 where R25, q and R6 are as defined above.
R3 may also particularly represent C(X3)xe2x95x90N(CH2)qR6 or where X3, q and R6 are as defined above.
R3 may also particularly represent xe2x80x94CH(X4)xe2x80x94CH2R6 where X4 and R6 are as defined above.
R3 may also particularly represent 
where R30 and R32 are hydrogen and R31 is xe2x80x94CO2H or xe2x80x94CONHOH.
R3 may also particularly represent 
R3 may also particularly represent 
R3 may also particularly represent 
R3 may also particularly represent 
where R33 is CN, s is zero and Z3 is an oxygen atom.
R3 may also particularly represent 
where R33 is CN, s is zero and Z3 is an oxygen atom.
R3 may also particularly represent 
where R33 is CN, s is zero, R35 is hydrogen and R36 is CO2H.
R3 may also particularly represent 
where R33 is CN, s is zero and
R5 is hydrogen or C1-4alkyl, especially methyl.
R3 may also particularly represent 
where R33 is CN, s is zero and
R5 is hydrogen or C1-4alkyl, especially methyl.
R3 may also particularly represent 
where W is NR39 [where R39 is C1-4alkyl, especially methyl] and R37 is CONHR5 [where R5 is heteroarylalkyl, especially pyridylmethyl].
R3 may also particularly represent 
where W is CH2 and R37 is hydrogen.
R3 may also particularly represent 
where W is CH2 and R38 is hydroxymethyl.
R3 may also particularly represent 
where W is CH2 and R38 is carboxy.
R3 may also particularly represent 
where R37 is hydrogen.
R3 may also particularly represent 
where R37 and R39 are alkoxycarbonyl.
R3 may also particularly represent 
where R37 is hydroxy and R39 is hydrogen.
R3 may also particularly represent 
where R40 is hydrogen, R41 is C1-4alkoxycarbonyl, especially methyl, R42 is C1-4alkyl, especially methyl, and R38 is C1-4acyl, especially acetyl.
R3 may also particularly represent 
where Y is defined above.
The moiety A1 may particularly represent a direct bond or a straight- or branched-chain alkylene linkage containing from 1 to 6 carbon atoms, optionally substituted by alkoxy.
Z1 may particularly represents an oxygen atom.
Z1 may also particularly represents a direct bond.
The moiety R3 is preferably xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94OCH2R6 wherein R6 represents an optionally substituted azaheteroaryl group, especially a pyridyl or isoxazolyl, substituted (by one or two methyl groups or halogen, e.g. chlorine atoms) on one or both, more preferably both, of the positions adjacent to the position of attachment of R6 to the rest of the molecule. Particular examples of R6 include a 3,5-dimethyl- or 3,5-dihalopyrid-4-yl moiety (more especially a 3,5-dimethylpyrid-4-yl moiety) or 3,5-dimethyl-isoxazol-4-yl.
It is to be understood that the aforementioned heteroaryl moieties present within R3 when containing at least one nitrogen atom may be presented as the corresponding N-oxides, and such N-oxides are also preferred. Thus, R3 may preferably contain a 3,5-dialkyl- or 3,5-dihalo-1-oxido-4-pyridinio group, such as a 3,5-dimethyl- or 3,5-dichloro-1-oxido-4-pyridinio group.
In compounds of formula (I) ring 
may particularly represent a 5-membered azaheterocycle containing at least one nitrogen atom, and ring 
may particularly represent a 6-membered azaheteroaryl or preferably a benzene ring. Such compounds in which n is zero and m is 1 are preferred.
The bicycle 
may particularly represent 
where Q1 is a CH or CX5 linkage (where X5 is halogen), or a nitrogen atom, or N+xe2x80x94Oxe2x88x92, especially a CH linkage, and the moiety 
especially where R5 represents a hydrogen atom or a methyl group, more especially where R5 is hydrogen. Preferred compounds have R2A1 attached to position 2 of the benzimidazole ring.
It will be appreciated that compounds of formula (I) in which the bicycle 
represents 
where the moiety 
where R5 represents a hydrogen atom, are tautomers.
The bicycle 
may also particularly represent 
especially where R2A1 is attached to the ring nitrogen atom.
The bicycle 
may also particularly represent 
especially where R2A1 is attached to the ring nitrogen atom.
The bicycle 
may also particularly represent 
(wherein Z is as hereinbefore defined, especially an oxygen atom) especially where R2A1 is attached to position 2 of the benzoxazole ring.
The bicycle 
may also particularly represent 
especially where R2A1 is attached to the ring nitrogen atom.
The bicycle 
may also particularly represent 
especially where R2A1 is attached to position 2 of the quinoline ring.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
A further particular group of compounds of the present invention are compounds of formula (Ia): 
wherein R1, R2, R3, A1, 
Z1 and Q1 are as defined previously, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ia) and N-oxides thereof, and their prodrugs.
Compounds of formula (Ia) in which R1 represents C1-4alkyl optionally substituted by one or more halogen atoms (especially methyl or difluoromethyl) are preferred.
Compounds of formula (Ia) in which R2 represents a straight- or branched-chain C1-4alkyl group (e.g. isopropyl), or cycloalkyl (e.g. cyclopropyl), alkoxy (e.g. methoxy), aryl, aryloxy or heteroaryl (e.g. pyridyl) are preferred.
Compounds of formula (Ia) in which R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 represents a disubstituted azaheteroaryl group, or an N-oxide thereof, more particularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are preferred. Azaheteroaryl groups substituted on both of the positions adjacent to the position of attachment of R6 to the rest of the molecule, for example 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are most preferred.
Compounds of formula (Ia) in which A1 represents a direct bond are a preferred group of compounds.
Compounds of formula (Ia) in which A1 represents a straight or branched chain alkylene linkage containing from 1 to 6 carbon atoms, for example a methylene, ethylene, propylene, methylmethylene, or butylmethylene linkage, (especially methylene) are also a preferred group of compounds.
Compounds of formula (Ia) in which A1 represents a straight or branched chain alkylene linkage containing from 1 to 6 carbon atoms which is substituted by alkoxy, for example a methoxymethylene or methoxypropylmethylene, are a further preferred group of compounds.
Compounds of formula (Ia) in which the moiety 
where R5 represents a hydrogen atom or a methyl group (especially a hydrogen atom) are preferred.
Compounds of formula (Ia) in which Q1 is a CH linkage are preferred.
Compounds of formula (Ia) in which Z1 is an oxygen atom are preferred.
A preferred group of compounds of the invention are compounds of formula (Ia) in which: R1 is methyl or difluoromethyl; R2 is C1-4alkyl (e.g. isopropyl), C3-6cycloalkyl (e.g. cyclopropyl), C1-4alkoxy (e.g. methoxy), aryl, aryloxy or azaheteroaryl; R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 is a dimethyl- or dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A1 is a direct bond or a methylene linkage; 
is 
Q1 is a CH linkage and Z1 is an oxygen atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ia) and N-oxides thereof, and their prodrugs.
A further particular group of compounds of the present invention are compounds of formula (Ib): 
wherein R1, R2, R3, A1 and Z1 are as defined previously, and Q represents a CH linkage or a nitrogen atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ib) and N-oxides thereof, and their prodrugs.
Compounds of formula (Ib) in which R1 represents methyl is preferred.
Compounds of formula (Ib) in which R2 represents a straight- or branched-chain C4-9alkyl group (e.g. heptyl), a cycloalkyl group (e.g. cyclopentyl, cyclohexyl), an aryl (e.g. optionally substituted phenyl), a heteroaryl (e.g. optionally substituted thienyl) or heterocycloalkyl (e.g. tetrahydofuranyl, tetrahydropyranylmethyl) are preferred.
Compounds of formula (Ib) in which R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 represents a disubstituted azaheteroaryl group, or a N-oxide thereof, more particularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are preferred. Azaheteroaryl groups substituted on both of the positions adjacent to the position of attachment of R6 to the rest of the molecule, for example 3,5-dimethyl-isoxazolyl, or 3,5-dimethyl- or 3,5-chloro-pyridyl or an N-oxide thereof, are most preferred.
Compounds of formula (Ib) in which A1 represents a direct bond are a preferred group of compounds.
Compounds of formula (Ib) in which A1 represents a straight or branched chain alkylene linkage containing from 1 to 6 carbon atoms, for example a methylene, ethylene, propylene, methylmethylene, butylmethylene linkage, (especially methylene) are also a preferred group of compounds.
Compounds of formula (Ib) in which Q represents a CH linkage or a nitrogen atom are preferred.
Compounds of formula (Ib) in which Z1 represents a direct bond are preferred.
A preferred group of compounds of the invention are compounds of formula (Ib) in which: R1 is hydrogen or methyl; R2 is C4-9alkyl (e.g. heptyl), C3-7cycloalkyl (e.g. cyclopentyl, cyclohexyl), aryl, heteroaryl (e.g. optionally substituted thienyl), heterocycloalkyl (e.g. tetrahydofuranyl, tetrahydropyranylmethyl); R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 is a dimethyl- or dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A1 is a direct bond or a methylene linkage and Z1 is a direct bond and Q is a CH linkage or a nitrogen atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ib) and N-oxides thereof, and their prodrugs.
A further particular group of compounds of the present invention are compounds of formula (Ic): 
wherein R1, R2, R3, A1, Q1, Z and Z1 are as defined previously, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ic) and N-oxides thereof, and their prodrugs.
Compounds of formula (Ic) in which R1 represents methyl or difluoromethyl are preferred.
Compounds of formula (Ic) in which R2 represents a straight- or branched-chain C1-4alkyl group (e.g. isopropyl), a cycloalkyl group (e.g. cyclopropyl), alkoxy (e.g. methoxy), aryl, aryloxy, heteroaryl (e.g. pyridyl) are preferred.
Compounds of formula (Ic) in which R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 represents a disubstituted azaheteroaryl group, or a N-oxide thereof, more particularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are preferred. Azaheteroaryl groups substituted on both of the positions adjacent to the position of attachment of R6 to the rest of the molecule, for example 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are most preferred.
Compounds of formula (Ic) in which A1 represents a direct bond are a preferred group of compounds.
Compounds of formula (Ic) in which A1 represents a straight or branched chain alkylene linkage containing from 1 to 6 carbon atoms, for example a methylene, ethylene, propylene, methylmethylene, or butylmethylene linkage, (especially methylene) are also a preferred group of compounds.
Compounds of formula (Ic) in which A1 represents a straight or branched chain alkylene linkage containing from 1 to 6 carbon atoms which is substituted by alkoxy, for example a methoxymethylene or methoxypropylmethylene, are a further preferred group of compounds.
Compounds of formula (Ic) in which Q1 is a CH linkage are preferred.
Compounds of formula (Ic) in which Z is an oxygen atom are preferred.
Compounds of formula (Ic) in which Z1 is an oxygen atom are preferred.
A preferred group of compounds of the invention are compounds of formula (Ic) in which: R1 is methyl or difluoromethyl; R2 is C1-4alkyl (e.g. isopropyl), C3-6cycloalkyl (e.g. cyclopropyl), C1-4alkoxy (e.g. methoxy), aryl, aryloxy or azaheteroaryl; R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 is a dimethyl- or dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A1 is a direct bond or a methylene linkage; Q1 is a CH linkage; and Z and Z1 are both oxygen atoms, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ic) and N-oxides thereof, and their prodrugs.
A further particular group of compounds of the present invention are compounds of formula (Id): 
wherein R1, R2, R3, A1, Q1, Z and Z1 are as defined previously, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Id) and N-oxides thereof, and their prodrugs.
Compounds of formula (Id) in which R1 represents methyl or difluoromethyl are preferred.
Compounds of formula (Id) in which R2 represents a straight- or branched-chain C1-4alkyl group (e.g. isopropyl), a cycloalkyl group (e.g. cyclopropyl), alkoxy (e.g. methoxy), aryl, aryloxy, heteroaryl (e.g. pyridyl) are preferred.
Compounds of formula (Id) in which R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 represents a disubstituted azaheteroaryl group, or a N-oxide thereof, more particularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are preferred. Azaheteroaryl groups substituted on both of the positions adjacent to the position of attachment of R6 to the rest of the molecule, for example 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are most preferred.
Compounds of formula (Id) in which A1 represents a direct bond are a preferred group of compounds.
Compounds of formula (Id) in which A1 represents a straight or branched chain alkylene linkage containing from to 6 carbon atoms, for example a methylene, ethylene, propylene, methylmethylene, or butylmethylene linkage, (especially methylene) are also a preferred group of compounds.
Compounds of formula (Id) in which A1 represents a straight or branched chain alkylene linkage containing from 1 to 6 carbon atoms which is substituted by alkoxy, for example a methoxymethylene or methoxypropylmethylene, are a further preferred group of compounds.
Compounds of formula (Id) in which Q1 is a CH linkage are preferred.
Compounds of formula (Id) in which Z is an oxygen atom are preferred.
Compounds of formula (Id) in which Z1 is an oxygen atom are preferred.
A preferred group of compounds of the invention are compounds of formula (Id) in which: R1 is methyl or difluoromethyl; R2 is C1-4alkyl (e.g. isopropyl), C3-6cycloalkyl (e.g. cyclopropyl), C1-4alkoxy (e.g. methoxy), aryl, aryloxy or azaheteroaryl; R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 is a dimethyl- or dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A1 is a direct bond or a methylene linkage; Q1 is a CH linkage; and Z and Z1 are both oxygen atoms, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Id) and N-oxides thereof, and their prodrugs.
A further particular group of compounds of the present invention are compounds of formula (Ie): 
wherein R1, R2, R3, A1 and Z1 are as defined previously, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ie) and N-oxides thereof, and their prodrugs.
Compounds of formula (Ie) in which R1 represents methyl are preferred.
Compounds of formula (Ie) in which R2 represents a straight- or branched-chain C4-9alkyl group (e.g. heptyl) a cycloalkyl group (e.g. cyclopentyl, cyclohexyl), an aryl (e.g. optionally substituted phenyl), a heteroaryl (e.g. optionally substituted thienyl) or heterocycloalkyl (e.g. tetrahydofuranyl, tetrahydropyranylmethyl) are preferred.
Compounds of formula (Ie) in which R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 represents a disubstituted azaheteroaryl group, or a N-oxide thereof, more particularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are preferred. Azaheteroaryl groups substituted on both of the positions adjacent to the position of attachment of R6 to the rest of the molecule, for example 3,5-dimethyl-isoxazolyl, or 3,5-dimethyl- or 3,5-chloro-pyridyl or an N-oxide thereof, are most preferred.
Compounds of formula (Ie) in which A1 represents a direct bond are a preferred group of compounds.
Compounds of formula (Ie) in which A1 represents a straight or branched chain alkylene linkage containing from 1 to 6 carbon atoms, for example a methylene, ethylene, propylene, methylmethylene, butylmethylene linkage, (especially methylene) are also a preferred group of compounds.
Compounds of formula (Ie) in which Z1 represents a direct bond are preferred.
A preferred group of compounds of the invention are compounds of formula (Ie) in which: R1 is hydrogen or methyl; R2 is C4-9alkyl (e.g. heptyl), C3-7cycloalkyl (e.g. cyclopentyl, cyclohexyl), aryl, heteroaryl (e.g. optionally substituted thienyl) or heterocycloalkyl (e.g. tetrahydofuranyl, tetrahydropyranylmethyl); R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 is a dimethyl- or dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A1 is a direct bond or a methylene linkage and Z1 is a direct bond, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ie) and N-oxides thereof, and their prodrugs.
A further particular group of compounds of the present invention are compounds of formula (If): 
wherein R1, R2. R3, A1 and Z1 are as defined previously, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (If) and N-oxides thereof, and their prodrugs.
Compounds of formula (If) in which R1 represents methyl or difluoromethyl are preferred.
Compounds of formula (If) in which R2 represents a straight- or branched-chain C1-4alkyl group (e.g. propyl), a cycloalkyl group (e.g. cyclopropyl), aryl, heteroaryl, or heterocycloalkyl are preferred.
Compounds of formula (If) in which R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 represents a disubstituted azaheteroaryl group, or a N-oxide thereof, more particularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are preferred. Azaheteroaryl groups substituted on both of the positions adjacent to the position of attachment of R6 to the rest of the molecule, for example 3,5-dimethyl-isoxazolyl, or 3,5-dimethyl- or 3,5-chloro-pyridyl or an N-oxide thereof, are most preferred.
Compounds of formula (If) in which A1 represents a direct bond are a preferred group of compounds.
Compounds of formula (If) in which A1 represents a straight or branched chain alkylene linkage containing from 1 to 6 carbon atoms, for example a methylene, ethylene, propylene, methylmethylene, butylmethylene linkage, (especially methylene) are also a preferred group of compounds.
Compounds of formula (If) in which Z1 represents an oxygen atom are preferred.
A preferred group of compounds of the invention are compounds of formula (If) in which: R1 is hydrogen or methyl; R2 is C1-4alkyl (e.g. propyl), C3-7cycloalkyl (e.g. cyclopentyl, cyclohexyl), aryl, heteroaryl or heterocycloalkyl; R3 represents xe2x80x94C(xe2x95x90O)xe2x80x94NHR6, xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 or xe2x80x94Oxe2x80x94CH2R6 where R6 is dimethyl- or dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A1 is a direct bond or a methylene linkage and Z1 is an oxygen atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (If) and N-oxides thereof, and their prodrugs.
A further preferred group of compounds of the invention are compounds of formula (Ig): 
wherein
R1 represents hydrogen, or a straight- or branched-chain alkyl group of 1 to about 4 carbon atoms, optionally substituted by one or more halogen atoms;
R2 represents hydrogen, alkoxy, alkyl, alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl, arylsulphonyl, arylthio, cycloalkenyl, cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, hydroxy, xe2x80x94SO2NR4R5, xe2x80x94NR4SO2R5, xe2x80x94NR4R5, xe2x80x94C(xe2x95x90C(xe2x95x90O)C(xe2x95x90O)R5; xe2x80x94C(xe2x95x90O)NR4R5, xe2x80x94C(xe2x95x90O)OR5, xe2x80x94O(Cxe2x95x90O)NR4R5, or xe2x80x94NR4C(xe2x95x90O)R5 where R4 and R5, which may be the same or different, each represent a hydrogen atom, or an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group;
R3 represents a group selected from:
xe2x80x94C(xe2x95x90Z)xe2x80x94N(Ra)R6xe2x80x83xe2x80x83(i)
xe2x80x94C(xe2x95x90Z)xe2x80x94CH2R6xe2x80x83xe2x80x83(ii)
xe2x80x94C(xe2x95x90Z)xe2x80x94R6xe2x80x83xe2x80x83(iii)
xe2x80x94CR7xe2x95x90C(R8)(CH2)nxe2x80x94R6xe2x80x83xe2x80x83(iv)
xe2x80x94C(R9)xe2x95x90C(R10)R11xe2x80x83xe2x80x83(v)
xe2x80x94C(R12)(R9)C(R10)(R13)R11xe2x80x83xe2x80x83(vi)
xe2x80x94C(R7)(R14)CH(R8)(CH2)nxe2x80x94R6xe2x80x83xe2x80x83(vii)
xe2x80x94R6xe2x80x83xe2x80x83(viii)
xe2x80x83xe2x80x94N(R15)C(xe2x95x90Z)R6xe2x80x83xe2x80x83(ix)
xe2x80x94C(CH3)xe2x95x90Nxe2x80x94OC(xe2x95x90O)NH2xe2x80x83xe2x80x83(x)
xe2x80x94C(xe2x95x90O)xe2x80x94N(CH3)OCH3xe2x80x83xe2x80x83(xi)
xe2x80x94Cxe2x89xa1Cxe2x80x94R6xe2x80x83xe2x80x83(xii)
xe2x80x94CH2xe2x80x94C(xe2x95x90Z)xe2x80x94R6xe2x80x83xe2x80x83(xiii)
xe2x80x94C(xe2x95x90Z)xe2x80x94C(xe2x95x90Z)R6xe2x80x83xe2x80x83(xiv)
xe2x80x94CH2xe2x80x94NHR6xe2x80x83xe2x80x83(xv)
xe2x80x94CH2xe2x80x94ZR6xe2x80x83xe2x80x83(xvi)
xe2x80x94CF2xe2x80x94OR6xe2x80x83xe2x80x83(xvii)
xe2x80x94NHxe2x80x94CH2R6xe2x80x83xe2x80x83(xviii)
xe2x80x94Zxe2x80x94CH2R6xe2x80x83xe2x80x83(xix)
xe2x80x94SOxe2x80x94CH2R6xe2x80x83xe2x80x83(xx)
xe2x80x94SO2xe2x80x94CH2R6xe2x80x83xe2x80x83(xxi)
xe2x80x94Oxe2x80x94CF2R6xe2x80x83xe2x80x83(xxii)
xe2x80x94Oxe2x80x94C(xe2x95x90Z)R6xe2x80x83xe2x80x83(xxiii)
xe2x80x94Nxe2x95x90Nxe2x80x94R6xe2x80x83xe2x80x83(xxiv)
xe2x80x94NHxe2x80x94SO2R6xe2x80x83xe2x80x83(xxv)
xe2x80x94SO2xe2x80x94NHR6xe2x80x83xe2x80x83(xxvi)
xe2x80x94CZxe2x80x94CZxe2x80x94NHR6xe2x80x83xe2x80x83(xxvii)
xe2x80x94NHxe2x80x94COxe2x80x94OR6xe2x80x83xe2x80x83(xxviii)
xe2x80x94Oxe2x80x94COxe2x80x94NHR6xe2x80x83xe2x80x83(xxix)
xe2x80x94NHxe2x80x94COxe2x80x94NHR6xe2x80x83xe2x80x83(xxx)
xe2x80x94R16xe2x80x83xe2x80x83(xxxi)
xe2x80x94CX2xe2x95x90CX3R6xe2x80x83xe2x80x83(xxxii)
[where Ra is a hydrogen atom or alkyl, hydroxy or amino;
R6 is aryl or heteroaryl;
R7 and R8, which may be the same or different, is each a hydrogen atom or alkyl, xe2x80x94CO2R17 (where R17 is hydrogen or an alkyl, arylalkyl or aryl group), xe2x80x94C(xe2x95x90Z)NR18R19 (where R18 and R19 may be the same or different and each is as described for R17), xe2x80x94CN or xe2x80x94CH2CN;
n is zero or an integer 1, 2 or 3;
R9 and R10, which may be the same or different, is each a group xe2x80x94CH2)nR6;
R11 is a hydrogen atom or alkyl;
R12 is a hydrogen or halogen atom or an xe2x80x94OR20 group (where R20 is a hydrogen atom or an alkyl, alkenyl, alkoxyalkyl or acyl group, or carboxamido or thiocarboxamido group);
R13 represents hydrogen or alkyl;
R14 is hydrogen or hydroxyl;
R15 is hydrogen, alkyl, amino, aryl, arylalkyl, or hydroxy; 
where W is (CH2)m or NR22;
R21 and R22 which may be the same or different is each a hydrogen atom, alkyl, acyl, arylalkyl xe2x80x94CO2R7 heteroarylalkyl, aryl, or heteroaryl;
m is 1 to 4;
X2 and X3 which may be the same or different is each a hydrogen or fluorine atom;
Z represents an oxygen or sulphur atom];
A1 represents a direct bond, or a straight or branched C1-6alkylene chain optionally substituted by hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroayyl. 
where R23 represents a hydrogen atom or a C1-4straight- or branched-chain alkyl, aryl C1-4alkyl, heteroaryl or heteroarylC1-4alkyl group;
Z1 represents a direct bond, or an oxygen or sulphur atom, or NH;
Q1 represents a CH or CX1 linkage or a nitrogen atom; and
X1 represents a halogen atom;
and N-oxides thereof, and their prodrugs, pharmaceutically acceptable salts, and solvates (e.g. hydrates), thereof.
Particular compounds of the invention are selected from the following:
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenyl-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxamide;
2-benzyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
(RS)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;
(R)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;
(S)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-carboxamide;
(RS)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
(R)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
(S)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
(RS)xe2x80x94N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
(R)xe2x80x94N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
(S)xe2x80x94N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
(RS)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;
(R)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;
(S)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxamide;
(RS)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;
(R)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;
(S)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;
2-(4-bromobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
(RS)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;
(R)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;
(S)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;
2-(4-cyanobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[4-(3-pyridyl)benzyl]-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-carboxamide;
(RS)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(methoxyphenyl)methyl-3H-benzimidazole-4-carboxamide;
(R)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxyphenyl)methyl-3H-benzimidazole-4-carboxamide;
(S)xe2x80x94N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxyphenyl)methyl-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methyl-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxamide;
2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
2-benzyl-N-(3,5dichloro-4-pyridyl)3H-benzimidazole-4-carboxamide;
2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-1-methyl-benzimidazole-4-carboxamide;
2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(2,6-difluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(2,6-dibromophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(2,4,6-trifluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(2,6-dichlorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(3,5-dimethyl-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;
N-(3-chloro-4-pyridyl)-7-methoxy-2-propyl-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-8-methoxy-2-n-propyl quinoline-5-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;
1-butyloxycarbonyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-1H-indole-6-carboxamide;
1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-3-methyl-N-(4-pyridyl)-1H-indole-6-carboxamide;
1-benzyl-N-(4-hydroxyphenyl)-3-methyl-1H-indole-6-carboxamide;
1-(2-cyclohexyl)ethyl-3-methyl-N-(4-pyrimidinyl)-1H-indole-6-carboxamide;
1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-N-(3,5-dimethyl-[1,2,4]-triazol-4-yl)-3-methyl-1H-indole-6-carboxamide;
1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indoline-6-carboxamide;
1-(2-cyclopentyl-7-methoxy-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone;
2-(3,5-dichloro-4-pyridyl)-1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-ethanone;
2-(3,5-dichloro-pyridin-4-yl)-1-[1-(1-toluene-4-sulphonyl)-3-methyl-1H-indol-6-yl]-ethanone;
1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-2-(4-pyridyl)-ethanone;
1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone;
1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-propan-2-ol;
7-methoxy-2-methoxymethyl-4-[2-(4-pyridyl)ethyl]-3H-benzimidazole;
2-(4-carboxamidobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
[2-(3-chlorophenoxy)-pyridin-3-yl]-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-methanone;
2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;
4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimidazole; ethyl 5-(2-cyclopropyl-7-methoxy-benzimidazole-4-yl)pyridine-2-carboxylate;
2-cyclopropyl-7-methoxy-4-(4-morpholinosulphonyl)-3H-benzimidazole;
1-benzyl-7-methoxy-2-methoxymethyl-4-(2-(4-pyridyl)ethyl)-1H-benzimidazole;
1-cyclohexylmethyl-N-(3,5-dichloro-4-pydyl)-3-methyl-1H-indole-6-carboxamide;
1-2-cyclohexyl)ethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;
1-[3-(cyclohexyl)propyl]-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-heptyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydro-2H-pyra-2-yl)methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-2-yl)methyl-1H-indole-6-carboxamide;
N-(3,5-dichoro-4-pyridyl)-3-methyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-methoxy)cyclopentyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-chlorothiophen-2-yl)methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3,5-dimethylisoxazol-4-yl)methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-methyl-thiazol-4-yl)methyl-1H-indole-6-carboxamide;
methyl 5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indol-1-ylmethyl]-furan-2-carboxylate;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-morpholin-4-yl)ethyl-1H-indole-6-carboxamide;
methyl 5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indole-1-yl]-pentanoate;
N-(3,5-dichloro-4-pyridyl)-1-(4-trifluorobenzyl)-3-methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(4-methylsulphonylbenzyl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-1-(4-methoxycarbonylbenzyl)-3-methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-nitrobenzyl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-1-(biphenyl-4-yl)methyl-3-methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(1-benzyl-imidazol-2-yl)methyl-1H-indole-6-carboxamide;
N-(3,5-dichloro-pyridin-4-yl)-3-ethyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-pyridin-4-yl)-3-isopropyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyisopropyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;
N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide;
1-benzyl-4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one;
4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one;
1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-ethyl)-1H-indole;
cis- and trans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vinyl)-1H-indole;
6-(1-hydroxy-1-phenyl-2-pyridin-4-yl)ethyl-1-(4-methoxybenzyl)-3-methyl-1H-indole;
[1-(4-methoxy-benzyl)-3-methyl-1H-indol-6-yl]-phenyl methanone;
N-methoxy-1-(4-methoxybenzyl)-3-methyl-N-methyl-1H-indole-6-carboxamide;
1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indazole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-1-(4-methoxybenzyl)-3-methyl-1H-indazole-6-carboxamide;
N-(3,5-dichloro-4-pyridyl)-4-methoxy-2-methoxymethyl-benzoxazole-7-carboxamide;
N-(3,5-dichloro-4-pyridyl)-3-isopropyl-1-methyl-1H-indole-5-carboxamide; and the corresponding pyridine N-oxides, and their prodrugs and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
Preferred compounds of the invention include:
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidazole-4-carboxamide;
N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;
4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimidazole; and the corresponding pyridine N-oxides, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
A more preferred compound of the invention is:
2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole; and its corresponding pyridine N-oxide, and its prodrugs, and pharmaceutically acceptable salts, and solvates (e.g. hydrates) thereof.
The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
Compounds within the scope of the present invention exhibit marked pharmacological activities according to tests described in the literature which tests results are believed to correlate to pharmacological activity in humans and other mammals. Detailed in vitro and in vivo procedures are described hereinafter.
Compounds of the invention are inhibitors of tumor necrosis factor, especially TNF-alpha. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF, especially of TNF-alpha. For example, compounds of the present invention are useful in joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis. Additionally, the compounds are useful in the treatment of sepsis, septic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, asthma and other chronic pulmonary diseases, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejection and leprosy. Furthermore, the compounds are useful in the treatment of infections such as viral infections and parasitic infections, for example malaria such as cerebral malaria, fever and myalgias due to infection, HIV, AIDS, cachexia such as cachexia secondary to AIDS or to cancer.
Compounds of the invention are also cyclic AMP phosphodiesterase inhibitors, in particular type IV cyclic AMP phosphodiesterase inhibitors. Thus, in another embodiment of the invention, we provide compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase, especially type IV cyclic AMP phosphodiesterase. For example, compounds within the present invention are useful as bronchodilators and asthma-prophylactic agents and agents for the inhibition of eosinophil accumulation and of the function- of eosinophils, e.g. for the treatment of inflammatory airways disease, especially reversible airway obstruction or asthma, and for the treatment of other diseases and conditions characterised by, or having an etiology involving, morbid eosinophil accumulation. As further examples of conditions which can be ameliorated by the administration of inhibitors of cyclic AMP phosphodiesterase such as compounds of the invention there may be mentioned inflammatory diseases, such as atopic dermatitis, urticaria, allergic rhinitis, psoriasis, rheumatoid arthritis, inflammatory diseases (e.g. ulcerative colitis and Crohn""s disease), adult respiratory distress syndrome and diabetes insipidus, other proliferative skin diseases such as keratosis and various types of dermatitis, conditions associated with cerebral metabolic inhibition, such as cerebral senility, multi-infarct dementia, senile dementia (Alzheimer""s disease), and memory impairment associated with Parkinson""s disease, and conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke, and intermittent claudication.
Another group of conditions which may be treated with the compounds of the present invention includes diseases and disorders of the central nervous system such as brain trauma, ischaemia, Huntington""s disease and tardive dyskinaesia.
Other disease states which may be treated with the compounds of the present invention include pyresis, autoimmune diseases (e.g. systemic lupus erythematosus, allergic erythematosus, multiple sclerosis), type 1 diabetes mellitus, psoriasis, Beghet""s disease, anaphylactoid purpura nephritis, chronic glomerulonephritis and leukemia.
A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase or of TNF, especially TNF-alpha, for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. xe2x80x9cEffective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective in inhibiting cyclic AMP phosphodiesterase and/or TNF and thus producing the desired therapeutic effect.
According to another aspect of the invention, there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase, especially type IV cyclic AMP phosphodiesterase.
According to a further aspect of the invention, there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF, especially of TNF-alpha.
References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
For administration by inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
The compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
The compounds of the present invention may also be formulated for use in conjunction with other therapeutic agents such as agents which increase cyclic AMP production including xcex2-agonists and PGE2. It is to be understood that the present invention includes combinations of compounds of the present invention with one or more of the aforementioned therapeutic agents.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
In particular, compounds of the invention in which the moiety R3 is group (iv) may be prepared by methods similar to those described in WO 94/20455.
Compounds of the invention in which the moiety R3 is group (v) may be prepared by methods similar to those described in WO 94/14800.
Compounds of the invention in which the moiety R3 is group (vi) may be prepared by methods similar to those described in WO 94/14742.
Compounds of the invention in which the moiety R3 is group (vii) may be prepared by methods similar to those described in WO 94/20446.
Compounds of the invention in which the moiety R3 is group (viii) may be prepared by methods similar to those described in WO 94/10118 and WO 95/22520.
Compounds of the invention in which the moiety R3 is group (ix) may be prepared by methods similar to those described in WO 93/25517.
Compounds of the invention in which the moiety R3 is group (x) may be prepared by methods similar to those described in EP-A-0470805.
Compounds of the invention in which the moiety R3 is group (xxviii) may be prepared by methods similar to those described in WO 96/36595, WO 96/36596 and WO 96/36611.
Compounds of the invention in which the moiety R3 is group (xxxiii) wherein R23 is 
may be prepared by methods similar to those described in WO 95/14681.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
may be prepared by methods similar to those described in EP-A-0523513.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
may be prepared by methods similar to those described in EP-A-0510562.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
may be prepared by methods similar to those described in EP-A-0428313.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
may be prepared by methods similar to those described in U.S. Pat. No. 5,449,686.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
may be prepared by methods similar to those described in WO 95/09624.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
may be prepared by methods similar to those described in WO 93/19749.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
may be prepared by methods similar to those described in WO 95/03794.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
where W is CH2 and R37 is hydrogen, may be prepared by methods similar to those described in U.S. Pat. No. 5,420,154.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
where W is NR39 and R37 and R39 are as hereinbefore defined, may be prepared by methods similar to those described in EP-A-0511865.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
and R37 is hydrogen or xe2x80x94CO2Me, may be prepared by methods similar to those described by R. D. Miller and P. Goelitz, J. Org. Chem., 1981, 46, page 1616-1618.
Compounds of the invention in which moiety R3 is group (xxxiii) wherein R23 is 
and R37 and R39 are as hereinbefore defined, may be prepared by methods similar to those described in WO 95/08534.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Green and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of this invention may be represented by the formula (Iz):
T1xe2x80x94R3xe2x80x83xe2x80x83(Iz)
wherein R3 is as hereinbefore defined and T1 represents a group of the formula: 
wherein 
R1, R2, A1, Z1, n and m are as hereinbefore defined.
In a process (A), compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94NHR6 group in which R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (II):
T1xe2x80x94C(xe2x95x90O)X6xe2x80x83xe2x80x83(II)
wherein T1 is as hereinbefore defined and X6 represents an azido, O-benzotriazol-1-yl, or alkoxy group, such as methoxy, or a halogen atom, such as a bromine, or preferably, a chlorine atom, with compounds of the general formula (III):
R6NHR48xe2x80x83xe2x80x83(III)
wherein R6 is as hereinbefore described, including N-oxides of heteroaryl groups, and R48 represents a hydrogen atom or an alkanoyl, e.g. acetyl group. The reaction may be carried out in the presence of a base such as an alkali metal dialkyldihydroaluminate, e.g. sodium diethyldihydroaluminate or an alkali metal hydride, e.g. sodium hydride, or in the presence of trimethylaluminium, optionally in an inert solvent, or mixture of inert solvents, chosen from for example a halogenated hydrocarbon (such as dichloromethane), toluene, dimethylformamide, or an ether (e.g. diethyl ether or tetrahydrofuran), preferably at a temperature from 0xc2x0 C. to the reflux temperature or at the melting point of the reaction mixture. The use of sodium diethyldihydroaluminate is preferred when R6 represents a heteroaryl group containing at least one nitrogen atom.
As another example, in a process (B), compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 group in which R6 is as hereinbefore defined, together with compounds of formula (I) wherein R3 represents a xe2x80x94C(R13)(R10)C(R11)(R14)R12 group in which R10 and R11 each represents a xe2x80x94(CH2)pR6 group (where R6 is as hereinbefore defined and p is 1), R12 and R14 represent hydrogen atoms and R13 represents a hydroxy group, may be prepared by the reaction of compounds of the general formula (IV):
T1xe2x80x94CO2R49xe2x80x83xe2x80x83(IV)
wherein T1 is as hereinbefore defined and R49 represents a C1-5alkyl group with compounds of the general formula (V):
R6xe2x80x94CH3xe2x80x83xe2x80x83(V)
wherein R6 is as hereinbefore defined, in the presence of a strong base such as lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine), in an inert solvent, for example an ether, e.g. tetrahydrofuran, preferably at a temperature from xe2x88x9265xc2x0 C. to 0xc2x0 C.
Alternatively compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 group and R6 is as hereinbefore defined, may be prepared by the oxidation of compounds of the general formula (VI):
T1xe2x80x94CH(OH)CH2R6xe2x80x83xe2x80x83(VI)
wherein T1 and R6 are as hereinbefore defined, by the application or adaptation of known methods. The oxidation can be carried out, for example, by reaction with oxalyl chloride and dimethyl sulphoxide, in a solvent such as dichloromethane, and preferably at a temperature lower than xe2x88x9265xc2x0 C. These conditions are especially convenient for the preparation of compounds wherein Z1 represents a direct bond or an oxygen atom.
As another example, in a process (C), compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94R6 group and R6 is as hereinbefore defined may be prepared by reaction of compounds of formula (I), wherein R3 represents a group xe2x80x94C(xe2x95x90O)xe2x80x94N(CH3)OCH3, with compounds of the general formula (VII):
xe2x80x83R6xe2x80x94MgBrxe2x80x83xe2x80x83(VII)
wherein R6 is as hereinbefore defined, in an inert solvent, for example an ether, e.g. tetrahydrofuran, preferably at a temperature from about 0xc2x0 C. to about reflux temperature.
Alternatively, in a process (D), compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94R6 group and R6 is as hereinbefore defined may be prepared by reaction of compounds of formula (II), especially where X6 represents O-benzotriazolyl, with the anion derived from reaction of compounds of formula R6xe2x80x94Br (where R6 is as hereinbefore defined) and butyllithium. The reaction is carried out in an inert solvent such as an ether, e.g. tetrahydrofuran, and at a temperature at about xe2x88x9270xc2x0 C.
As another example, compounds of formula (I), wherein R3 represents a xe2x80x94CR8xe2x95x90C(R9)(CH2)pxe2x80x94R6 group and R6 R8, R9 and p are as hereinbefore defined, may be prepared by the reaction of compounds of formula (VIII):
T1xe2x80x94C(xe2x95x90O)R8xe2x80x83xe2x80x83(VIII)
wherein T1 and R8 are as hereinbefore defined, with the reaction product of a compound of the formula (IX):
[(R50)3PCH(R9)(CH2)pR6]+Xxe2x88x92xe2x80x83xe2x80x83(IX)
wherein R9 R6 and p are as hereinbefore defined, R50 represents an aryl, such as phenyl group, and X represents halo, preferably bromo, with a base such as an alkali metal alkoxide (for example potassium t-butoxide), or an alkali metal hydride (for example sodium hydride), or butyl lithium. The reaction is preferably carried out in a solvent such as dimethylformamide or tetrahydrofuran.
Compounds of formula (I) wherein R3 represents a xe2x80x94C(R10)xe2x95x90C(R11)R12 group and R10, R11 and R12 are as hereinbefore defined, may be similarly prepared by the reaction of compounds of formula (X):
T1xe2x80x94C(xe2x95x90O)R10xe2x80x83xe2x80x83(X)
wherein T1 and R10 are as hereinbefore defined, with the phosphorane obtained by treating a compound of the formula (XI):
[(R50)3PCH(R11)R12]+Xxe2x88x92xe2x80x83xe2x80x83(XI)
wherein R11 and R12 and R50 are as hereinbefore defined with a base as described above.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94CR8xe2x95x90C(R9)(CH2)pxe2x80x94R6 group, where R6, R8, R9 and p are as hereinbefore defined, may be prepared by the reaction of compounds of formula (VIII), wherein T1 is as hereinbefore defined, with the reaction product of a compound of the formula (XII):
(R51O)2P(xe2x95x90O)CH(R9)(CH2)pR6xe2x80x83xe2x80x83(XII)
wherein R6, R9 and p are as hereinbefore defined and R51 represents a C1-4alkyl group, with a base such as an alkali metal alkoxide (for example potassium t-butoxide), or an alkali metal hydride (for example sodium hydride). The reaction is preferably carried out in a solvent such as dimethylformamide or tetrahydrofuran. Compounds of formula (I) wherein R3 represents a xe2x80x94C(R10)xe2x95x90C(R11)R12 group and R10, R11 and R12 are as hereinbefore defined may be prepared in a similar manner to that described above from compounds of formula (X), wherein T1 and R10 are as hereinbefore defined, and compounds of formula (XIII):
(R51O)2P(xe2x95x90O)CH(R11)R12xe2x80x83xe2x80x83(XIII)
wherein R11, R12 and R51 are as hereinbefore defined.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94C(R10)xe2x95x90C(R11)R12 group where R10, R11 and R12 are as hereinbefore defined may also conveniently be prepared from compounds of formula (XIV):
T1xe2x80x94C(R10)(OH)CH(R11)R12xe2x80x83xe2x80x83(XIV)
wherein T1, R10, R11 and R12 are as hereinbefore defined, by dehydration using an acid such as a Lewis acid (e.g. thionyl bromide) at an elevated temperature, for example the reflux temperature, optionally in the presence of a suitable base such as 1,8-diazabicyclo-[5.4.0]undec-7-ene.
Compounds of formula (I) wherein R3 represents xe2x80x94C(R8)xe2x95x90C(R9)(CH2)pR6 where R6, R8, R9 and p are as hereinbefore defined may be prepared by dehydration of compounds of formula (XV):
T1xe2x80x94C(R8)(OH)CH(R9)(CH2)pR6xe2x80x83xe2x80x83(XV)
wherein T1, R6, R8, R9 and p are as hereinbefore defined, using an acid such as a Lewis acid (e.g. thionyl bromide) at an elevated temperature, for example the reflux temperature, optionally in the presence of a suitable base such as 1,8-diazabicyclo-[5.4.0]undec-7-ene. Alternatively the dehydration may be carried out using an acid catalyst, such as 4-toluenesulphonic acid, in an inert solvent, such as benzene, at a temperature from about 0xc2x0 C. to about reflux temperature.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94C(R13)(R10)C(R11)(R14)R12 group where R10, R11 and R12 are as hereinbefore defined, and R13 and R14 each represent a hydrogen atom, may be prepared by hydrogenation of compounds of the general formula (I) wherein R3 represents a xe2x80x94C(R10)xe2x95x90C(R11)R12 where R10, R11 and R12 are as hereinbefore defined. The hydrogenation may be carried out using hydrogen in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. Compounds of formula (I) wherein R3 represents a xe2x80x94C(R8)(R15)CH(R9)(CH2)pxe2x80x94R6 group where R8, R9 and p are as hereinbefore defined and R15 represents a hydrogen atom, may be prepared in a similar manner to that described above by hydrogenation of compounds of the general formula (I) wherein R3 represents a xe2x80x94C(R8)xe2x95x90C(R9)(CH2)pR6 where R8, R9 and p are as hereinbefore defined.
Compounds of formula (I), wherein R3 represents a xe2x80x94C(R8)(R15)CH(R9)(CH2)pxe2x80x94R6 group where R6 is as hereinbefore defined and R8, R9 and R15 represent hydrogen atoms and p is zero, may be prepared by reduction of compounds of the general formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6, where R6 is as hereinbefore defined. The reduction may be carried out with hydrazine hydrate, in the presence of an alkali metal hydroxide, such a potassium hydroxide, in an inert solvent, such as diethylene glycol, at a temperature up to about 100xc2x0 C.
As another example, compounds of formula (I) wherein R3 represents a R6 group may be prepared by the reaction of compounds of the general formula (XVI):
T1xe2x80x94B(OH)2xe2x80x83xe2x80x83(XVI)
wherein T1 is as hereinbefore defined, with a compound of the general formula (XVII):
R6xe2x80x94X7xe2x80x83xe2x80x83(XVII)
wherein R6 is as hereinbefore described and X7 represents a halogen atom for example a bromine or chlorine atom, or a triflate group, in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0).
Alternatively compounds of formula (I) wherein R3 represents a R6 group may be similarly prepared by the reaction of compounds of the general formula (XVIII):
T1-X7xe2x80x83xe2x80x83(XVIII)
wherein T1 and X7 are as hereinbefore defined, with a compound of the general formula (XIX):
R6xe2x80x94B(OH)2xe2x80x83xe2x80x83(XIX)
wherein R6 is as hereinbefore defined in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0).
Compounds of formula (I) wherein R3 represents a R6 group may also be prepared by reaction of compounds of formula (XVIII) wherein T1 is as hereinbefore defined and X7 is a bromine atom, with a solution of butyllithium in hexane, in an inert solvent such as tetrahydrofuran, at a temperature at about xe2x88x9270xc2x0 C., followed by reaction with tributyltin chloride and subsequent reaction of the tributyltin intermediate with compounds of formula (XVII) wherein R6 is as hereinbefore defined and X7 is a bromine atom, in the presence of bis(dibenzylidene)acetone palladium(0) and triphenylphosphine in dimethylformamide at a temperature up to about 120xc2x0 C.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94NHC(xe2x95x90O)R6 group where R6 is as hereinbefore defined, may be prepared by the reaction of compounds of the general formula (XX):
T1xe2x80x94NH2xe2x80x83xe2x80x83(XX)
wherein T1 is as hereinbefore defined with compounds of formula (XXII):
R6C(xe2x95x90O)X8xe2x80x83xe2x80x83(XXI)
wherein R6 is as hereinbefore defined and X8 represents an azido group or a halogen atom, e.g. bromine or, preferably, chlorine atom, are as hereinbefore defined, preferably in the presence of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94C(CH3)xe2x95x90Nxe2x80x94OC(xe2x95x90O)NH2 group may be prepared by the reaction of compounds of the general formula (XXII):
T1xe2x80x94C(xe2x95x90NOH)CH3xe2x80x83xe2x80x83(XXII)
wherein T1 is as hereinbefore defined, with sodium cyanate in an inert solvent such as dichloromethane in the presence of an acid such as acetic acid or trifluoroacetic acid at a temperature at about ambient temperature.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94N(Me)OCH3 group may be prepared by the reaction of compounds of the general formula (II), wherein T1 is as hereinbefore defined and X6 is a halogen atom, such as a chlorine atom, with N-methyl-O-methylhydroxylamine in an inert solvent such as dimethylformamide.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94Cxe2x89xa1Cxe2x80x94R6 group where R6 is as hereinbefore defined, may be prepared by the reaction of compounds of the general formula (XXIII):
T1xe2x80x94C(xe2x95x90NOH)CH3xe2x80x83xe2x80x83(XXIII)
wherein T1, is as hereinbefore defined , with acetylenes of the general formula (XXIV):
R6Cxe2x89xa1CHxe2x80x83xe2x80x83(XXIV)
wherein R6 is as hereinbefore defined. Preferably the reaction is carried out with the aid of a catalyst, e.g. palladium on carbon and cuprous iodide, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dimethylformamide.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94R6 group where R6 is as hereinbefore defined may be prepared by oxidation of compounds of the general formula (XXV):
T1xe2x80x94CH2CH(OH)R6xe2x80x83xe2x80x83(XXV)
wherein T1 and R6 are as hereinbefore defined. The oxidation may conveniently be carried out, for example, by reaction with oxalyl chloride and dimethyl sulphoxide, in a solvent such as dichloromethane, and preferably at a temperature lower than xe2x88x9265xc2x0 C. Alternatively, the oxidation may be carried out by reaction with chromium trioxide in the presence of 3,5-dimethylpyrazole.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)R6 group where R6 is as hereinbefore defined may be prepared by the oxidation of compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94CH2R6 group where R6 is as hereinbefore defined. The oxidation may be carried out, for example, by reaction with pyridinium dichromate, preferably in a solvent such as dichloromethane. This reaction is particularly suitable for the preparation of compounds wherein R6 represents a heteroaryl, for example an optionally substituted pyridyl, group.
As another example, compounds of formula (I) wherein R3 represents xe2x80x94CH2xe2x80x94NHR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXVI):
T1xe2x80x94C(xe2x95x90O)Hxe2x80x83xe2x80x83(XXVI)
wherein T1 is as hereinbefore defined, with compounds of formula (III) wherein R6 is as hereinbefore defined and R48 is hydrogen, followed by reduction with sodium cyanoborohydride. This reaction is especially suitable for the preparation of compounds wherein R6 represents an optionally substituted phenyl or naphthyl group.
Alternatively, compounds of formula (I) wherein R3 represents xe2x80x94CH2xe2x80x94NHR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXVII):
T1xe2x80x94CH2X9xe2x80x83xe2x80x83(XXVII)
wherein T1 is as hereinbefore defined and X9 represents halogen, preferably a bromine atom, with compounds of formula (III) wherein R6 is as hereinbefore defined and R48 is hydrogen. The reaction preferably takes place in the presence of a base such as sodium hydride. The reaction is especially suitable for the preparation of compounds wherein R6 represents an optionally substituted heteroaryl group.
As another example, compounds of formula (I) wherein R3 represents xe2x80x94CH2xe2x80x94OR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXVII) wherein T1 and X9 are as hereinbefore defined with compounds of formula (XXVIII):
R6xe2x80x94OHxe2x80x83xe2x80x83(XXVIII)
wherein R6 is as hereinbefore defined, preferably with the aid of a base such as an alkali metal alkoxide, e.g. potassium t-butoxide.
Alternatively compounds of formula (I) wherein R3 represents a xe2x80x94CH2xe2x80x94OR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXIX):
T1xe2x80x94CH2OHxe2x80x83xe2x80x83(XXIX)
wherein T1 is as hereinbefore defined with compounds of formula (XVII) wherein R6 and X7 are as hereinbefore defined, preferably with the aid of a base such as an alkali metal alkoxide, e.g. potassium t-butoxide. The reaction is preferably, carried out in a solvent such as tetrahydrofuran.
Alternatively compounds of formula (I) wherein R3 represents a xe2x80x94CH2xe2x80x94OR6 group where R6 is as hereinbefore defined may be prepared by reaction of compounds of the general formula (XXIX) with compounds of formula (XXVIII) wherein R6 is as hereinbefore defined, in the presence of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, and triphenylphosphine, preferably in a dry ethereal solvent, e.g. diethyl ether or tetrahydrofuran, preferably at or near room temperature.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94CH2xe2x80x94SR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXVII), wherein T1 and X9 are as hereinbefore defined with compounds of the general formula (XXX):
R6xe2x80x94SHxe2x80x83xe2x80x83(XXX)
wherein R6 is as hereinbefore defined, preferably with the aid of a base such as an alkali metal carbonate, e.g. potassium carbonate.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94CF2xe2x80x94OR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXI):
T1xe2x80x94CF2Brxe2x80x83xe2x80x83(XXXI)
with compounds of the general formula (XXVIII) wherein R6 is as hereinbefore defined, preferably with the aid of a base such as sodium hydride, preferably in a solvent such as dimethylformamide.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94NHxe2x80x94CH2R6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XX) wherein T1 is as hereinbefore defined, with compounds of the general formula (XXXII):
R6CHOxe2x80x83xe2x80x83(XXXII)
wherein R6 is as hereinbefore defined, in the presence of a reducing agent such as sodium cyanoborohydride.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94Oxe2x80x94CH2R6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXIII):
T1xe2x80x94OHxe2x80x83xe2x80x83(XXXIII)
wherein T1 is as hereinbefore defined, with compounds of the general formula (XXXIV):
R6CH2X10xe2x80x83xe2x80x83(XXXIV)
wherein R6 is as hereinbefore defined and X10 represents hydroxyor a halogen atom. When X10 represents hydroxy the reaction is conveniently carried out in the presence of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, and triphenylphosphine, preferably in a dry ethereal solvent, e.g. diethyl ether or tetrahydrofuran, preferably at or near room temperature. When X10 represents a halogen atom, especially a chlorine atom, the reaction is preferably carried out in the presence of a base such as an alkali metal carbonate, e.g. potassium carbonate, preferably in an solvent such as dimethylformamide, and at a temperature from about room temperature to about 80xc2x0 C.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94Sxe2x80x94CH2R6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXV):
xe2x80x83T1xe2x80x94SHxe2x80x83xe2x80x83(XXXV)
wherein T1 is as hereinbefore defined, with compounds of formula (XXXIV) wherein R6 is as hereinbefore defined and X10 is a halogen atom, preferably a bromine atom. The reaction is preferably carried out in the presence of a base such as an alkali metal alkoxide, e.g. sodium methoxide.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94Oxe2x80x94CF2R6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXIII) wherein T1 is as hereinbefore defined with compounds of the general formula (XXXVI):
R6CF2Brxe2x80x83xe2x80x83(XXXVI)
wherein R6 is as hereinbefore defined, preferably with the aid of a base such as sodium hydride, preferably in a solvent such as dimethylformamide.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94Oxe2x80x94C(xe2x95x90O)R6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXIII), wherein T1 is as hereinbefore defined, with compounds of the general formula (XXI) wherein R6 is as hereinbefore defined, and X8 represents a halogen atom, for example a bromine or, preferably, a chlorine atom, preferably in the presence of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
As another example, compounds of formula (I) wherein R3 represents a trans xe2x80x94Nxe2x95x90Nxe2x80x94R6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXVII):
T1xe2x80x94N2+BF4xe2x88x92xe2x80x83xe2x80x83(XXXVII)
wherein T1 is as hereinbefore defined, with compounds of the general formula (XXXVIII):
R6Hxe2x80x83xe2x80x83(XXXVIII)
wherein R6 is as hereinbefore defined, preferably with the aid of a base such as lithium diisopropylamide.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94NHxe2x80x94SO2R6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XX), wherein T1 is as hereinbefore defined, with compounds of the general formula (XXXIX):
R6SO2X11xe2x80x83xe2x80x83(XXXIX)
wherein R6 is as hereinbefore defined and X11 represents a halogen, preferably chlorine, atom, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as tetrahydrofuran.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94SO2xe2x80x94NR21R22 group where R21 and R22 are as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXX):
T1SO2Clxe2x80x83xe2x80x83(XXXX)
wherein T1 is as hereinbefore defined with compounds of the general formula (XXXXI):
R21xe2x80x94NHxe2x80x94R22xe2x80x83xe2x80x83(XXXXI)
wherein R21 and R22 are as hereinbefore defined, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as tetrahydrofuran.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94NHR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXXII):
T1xe2x80x94COCOOHxe2x80x83xe2x80x83(XXXXII)
wherein T1 is as hereinbefore defined, with thionyl chloride in an inert solvent such as dichloromethane, followed by reaction with compounds of formula (III) wherein R6 is as hereinbefore defined and R48 is hydrogen.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94NHxe2x80x94COxe2x80x94OR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXXIII):
xe2x80x83T1xe2x80x94NCOxe2x80x83xe2x80x83(XXXXIII)
wherein T1 is as hereinbefore defined, with compounds of formula (XXVIII) wherein R6 is as hereinbefore defined, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94Oxe2x80x94COxe2x80x94NHR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XXXIII) wherein T1 is as hereinbefore defined, with compounds of formula (III) wherein R6 is as hereinbefore defined and R48 is hydrogen, together with phosgene or a source thereof, preferably, bis(trichloromethyl)carbonate, preferably with the aid of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
As another example, compounds of formula (I) wherein R3 represents a xe2x80x94NHxe2x80x94COxe2x80x94NHR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of the general formula (XX), wherein T1 is as hereinbefore defined with compounds of the general formula (XXXXIV):
R6NCOxe2x80x83xe2x80x83(XXXXIV)
wherein R6 is as hereinbefore defined, preferably in the presence of a base such as a tertiary amine, e.g. triethylamine, preferably in a solvent such as dichloromethane.
According to a further feature of the present invention, compounds of formula (I) wherein R3 represents a xe2x80x94NHxe2x80x94COxe2x80x94NHR6 group where R6 is as hereinbefore defined may be prepared by the reaction of compounds of formula (XX) wherein T1 is as hereinbefore defined with compounds of formula (III) wherein R6 is as hereinbefore defined and R48 is hydrogen, together with phosgene or a source thereof. The reaction is preferably carried out by reacting the compound of formula (XX) with phosgene or, preferably, bis(trichloromethyl) carbonate, and by then reacting the product of that reaction with the anion derived from the compound of formula (III), for example by reaction with a base such as sodium hydride. The reactions may be preferably carried out in suitable solvents such as dichloromethane and tetrahydrofuran.
According to a further feature of the present invention, compounds of formula (Ia)
wherein 
A1, R1, R2, R3, Q1 and Z1 are as hereinbefore defined, (with the proviso that when A1 a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be prepared by reaction of compounds of formula (XXXXV): 
wherein A1, R1, R2, R3, Q1 and Z1 are as hereinbefore defined, (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), with sodium hypochlorite in the presence of an aqueous acid such as dilute hydrochloric acid, in an alcohol, such as methanol, and at a temperature at about ambient temperature, followed by treatment with an alkali metal carbonate, such as sodium carbonate, at a temperature of about reflux temperature.
According to a further feature of the present invention, compounds of formula (Ia),
wherein 
A1, R1, R2, R3, Q1 and Z1 are as hereinbefore defined, (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be prepared by reaction of compounds of formula (XXXXVI): 
wherein R1, R3, Q1 and Z1 are as hereinbefore described, with compounds of formula (XXXXVII):
R2A1C(xe2x95x90O)X12xe2x80x83xe2x80x83(XXXXVII)
wherein R2 and A1 are as hereinbefore defined, (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), and X12 represents a hydroxy group or a halogen atom, preferably a chlorine atom. When X12 represents a hydroxy group the reaction is preferably carried out in the hydrochloric acid at a temperature at about 125xc2x0 C. When X12 represents a halogen atom the reaction is preferably carried out in an inert solvent, such as dichloromethane, optionally in the presence of triethylamine and at a temperature from about 0xc2x0 C. to about ambient temperature, followed by reaction of the product with acetic acid at a temperature at about reflux.
According to a further feature of the present invention, compounds of formula (Ia), wherein R1, R3, Q1 and Z1 are as hereinbefore defined, R2 represents a C1-5alkoxy group optionally substituted by one or more fluorine atoms, A1 represents a direct bond and 
may be prepared by reaction of compounds of formula (XXXXVI) wherein R1, R3, Q1 and Z1 are as hereinbefore described, with compounds of formula (XXXXVIII):
(R49O)4Cxe2x80x83xe2x80x83(XXXXVIII)
wherein R49 is a C1-5alkyl group optionally substituted by one or more fluorine atoms. The reaction may conveniently be carried out in acetic acid at a temperature up to about reflux temperature.
As another example, compounds of formula (Ia) wherein 
R1, R3, Q1 and Z1 are as hereinbefore described, R2 is alkylthio, arylthio or arylalkylthio and A1 represents a direct bond, may be prepared by reaction of compounds of formula (XXXXIX): 
wherein 
R1, R3, Q1 and Z1 are as hereinbefore described, with the appropriate alkyl- or aryl- or arylalkylthiol. The reaction may conveniently be carried out in an inert solvent such as methanol or dimethylformamide, at a temperature from about room temperature to about 80xc2x0 C., optionally in the presence of an alkali metal carbonate, such as potassium carbonate.
Alternatively compounds of formula (Ia) wherein 
R1, R3, Q1 and Z1 are as hereinbefore described, R2 represents alkylthio or arylalkylthio and A1 represents a direct bond, may be prepared by reaction of compounds of formula (L): 
wherein R1, R3, 
Q1 and Z1 are as hereinbefore described, with the appropriate alkyl- or arylalkylhalide. The reaction may conveniently be carried out in an inert solvent such as methanol or dimethylformamide, at a temperature from about room temperature to about 80xc2x0 C., optionally in the presence of an alkali metal carbonate, such as potassium carbonate.
As another example, compounds of formula (Ia) wherein 
R1, R3, Q1 and Z1 are as hereinbefore described, R2 represents NR4R5 where R4 and R5 are as hereinbefore described and A1 represents a direct bond, may be prepared by reaction of compounds of formula (XXXXIX) wherein 
R1, R3, Q1 and Z1 are as hereinbefore described, with compounds of formula (LI):
HNR4R5xe2x80x83xe2x80x83(LI)
wherein R4 and R5 are as hereinbefore described. The reaction may conveniently be carried out in an inert solvent for example an alcohol such as isopropanol, at a temperature from about room temperature to about 80xc2x0 C., optionally in the presence of an alkali metal carbonate, such as potassium carbonate.
As another example, compounds of formula (Ia) wherein 
R1, R3, Q1 and Z1 are as hereinbefore described, R2 represents xe2x80x94C(xe2x95x90O)R5, in which R5 is aryl or heteroaryl, and A1 represents a direct bond, may be prepared by reaction of compounds of formula (LII): 
wherein R1, R3, 
Q1 and Z1 are as hereinbefore described, with compounds of formula (LIII):
R5C(xe2x95x90O)X13xe2x80x83xe2x80x83(LIII)
wherein R5 is aryl or heteroaryl and X13 is a chlorine atom. The reaction may conveniently be carried out in an inert solvent for example dimethylformamide, at a temperature up to about 150xc2x0 C., under vacuo, optionally in the presence of triethylamine.
As another example, compounds of formula (I) wherein R3 represents a 
group may be prepared by reaction of compounds of formula (I)
wherein R3 represents a 
in which R52 is a methyl or ethyl group, with hydroxylamine hydrochloride in the presence of sodium methoxide, in a solvent such as an alcohol, for example methanol, and at a temperature at about room temperature.
As another example, compounds of formula (I) wherein T1 is as hereinbefore described and the moiety R3 represents a 
group may be prepared by reaction of compounds of formula (VIII) wherein R8 is methyl, with glyoxylic acid monohydrate at about 100xc2x0 C. to 150xc2x0 C., followed by treatment with hydrazine hydrate at reflux.
As another example, compounds of formula (I) wherein R3 represents a 
group may be prepared by reaction of compounds of formula (LIV):
T1xe2x80x94C(CN)[(CH2)2CO2R52]2xe2x80x83xe2x80x83(LIV)
wherein T1 is as hereinbefore described and R52 is a methyl or an ethyl group, with an alkali metal hydride, for example sodium hydride, in an inert solvent, such as 1,2-dimethoxyethane, at a temperature at about reflux temperature, followed by heating the product with a mixture of concentrated hydrochloric acid and 20% sulphuric acid in ethanol at reflux temperature.
As another example, compounds of formula (I) wherein R3 represents a 
group may be prepared by reaction of compounds of formula (I), wherein T1 is as hereinbefore described and the moiety R3 represents a 
group, with diethyl aluminium cyanide in an inert solvent, such as toluene, and at a temperature at about room temperature.
Compounds of formula (I), wherein R3 represents a 
group may be prepared by reaction of compounds of formula (XVIII), wherein T1 is as hereinbefore described and X7 is a bromine atom, with an alkyl lithium, such as n-butyl lithium at xe2x88x9278xc2x0 C., in an inert solvent, such as tetrahydrofuran, followed by reaction with 3-methoxycyclohex-2-enone (prepared according to the method of A. J. Pearson et al., J. Org. Chem., 1984, 49, pages 3887-3891) at a temperature at about 0xc2x0 C.
As another example, compounds of formula (I) wherein R3 represents a 
group may be prepared by hydrolysis of compounds of formula (I)
wherein R3 represents a 
group, with an alkali metal hydroxide such as potassium hydroxide in an aqueous alcohol such as aqueous methanol and at a temperature from about room temperature to about reflux.
Compounds of formula (I), wherein R3 represents a 
group, may be prepared by reaction of compounds of formula (I), wherein R3 represents a 
group, with triflic anhydride in the presence of an appropriate tertiary amine base, or with lithium diisopropylamide at xe2x88x9278xc2x0 C., in an inert solvent such as tetrahydrofuran, followed by treatment with N-phenyl trifluorosulphonimide. The resulting enol triflate may then be reacted with carbon monoxide in an alcohol such as methanol, optionally mixed with dimethylformamide, in the presence of an amine, such as triethylamine, and an appropriate palladium catalyst, such as tetrakis(triphenylphosphine)palladium, at a temperature at about room temperature.
As another example, compounds of formula (I) wherein R3 represents a 
group, in which R39 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, may be prepared by reaction of compounds of formula (LV):
T1xe2x80x94CHxe2x95x90CHxe2x80x94CO2Hxe2x80x83xe2x80x83(LV)
wherein T1 is as hereinbefore described, with a hydrazine of formula (LVI):
R39NHxe2x80x94NH2xe2x80x83xe2x80x83(LVI)
wherein R39 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. The reaction is preferably carried out in an inert solvent , such as toluene, at a temperature at about 100xc2x0 C.
As another example, compounds of formula (I) wherein R3 represents a 
group may be prepared by reduction of compounds of the general formula (LVII):
T1xe2x80x94CH(CH2NO2)CH2CO2R49xe2x80x83xe2x80x83(LVII)
wherein T1 and R49 are as hereinbefore described, followed by hydrolysis with sodium hydroxide. The reduction may be carried out using hydrogen in the presence of Raney Nickel preferably in a solvent such as methanol or ethanol and at a temperature at about room temperature.
As another example, compounds of formula (I) wherein R3 represents a group 
may be prepared by oxidation of compounds of formula (LVIII):
T1xe2x80x94CH(NHCO2Me)CH2CH2CH2OHxe2x80x83xe2x80x83(LVIII)
wherein T1 is as hereinbefore described, with Jones reagent in acetone at room temperature.
According to a further feature of the present invention, in a process (E), compounds of the present invention of formula (Ia) wherein R1, R2, R3, A1, Q1 and Z1 are as hereinbefore defined, and 
may be prepared by deprotection of compounds of formula (LIX): 
wherein R1, R2, R3, A1, Q1 and Z1 are as hereinbefore defined and 
is a suitable protecting group, for example a 2-trimethylsilanyl-ethoxymethyl group. When 
is a 2-trimethylsilanyl-ethoxymethyl group the deprotection reaction may conveniently be carried out by treatment with hydrochloric acid, in an alcohol, such as ethanol, and at a temperature at about reflux temperature. This process is particularly convenient for compounds of formula (Ia) wherein R3 is a group xe2x80x94Oxe2x80x94CH2xe2x80x94R6 in which R6 is as hereinbefore defined.
According to a further feature of the present invention, in a process (F) compounds of the invention may be prepared by interconversion of other compounds of the invention.
For example compounds of the invention containing an imino group may be alkylated with an alkyl halide, alkyl halide or heteroarylalkyl halide. Thus compounds of formula (Ia) wherein 
and R5 represents C1-4straight- or branched-chain alkyl, an arylC1-4alkyl or a heteroarylC1-4alkyl group may be prepared by reaction of compounds of formula (Ia) wherein 
with a C1-4straight- or branched-chain alkyl halide, an arylC1-4alkyl halide or a heteroarylC1-4alkyl halide. The alkylation may for example be carried out in the presence of a base, such as an alkali metal hydride, e.g. sodium hydride, in dimethylformamide, or dimethyl sulphoxide, at a temperature from about 0xc2x0 C. to about 100xc2x0 C.
As another example of the interconversion process, compounds of the invention containing an imino group may be acylated with an acyl halide, aroyl halide or heteroaroyl halide. The acylation may for example be carried out in the presence of a suitable base, such as triethylamine or pyridine, optionally in dimethylformamide, at a temperature from about 0xc2x0 C. to about 100xc2x0 C.
As another example of the interconversion process, compounds of the invention containing a heterocyclic group wherein the hetero atom is a nitrogen atom may be oxidised to their corresponding N-oxides. This interconversion is especially convenient for the preparation of compounds of the invention wherein Z1 represents an oxygen atom and wherein neither R2 or R3 contain an oxidisable groups such as a thioether. The oxidation may conveniently be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90xc2x0 C. Alternatively, the oxidation may be carried out by reaction with a peracid, for example peracetic acid or m-chloroperoxybenzoic acid, in an inert solvent such as chloroform or dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. The oxidation may alternatively be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60xc2x0 C.
As another example of the interconversion process, an N-oxide group within a compound of formula (I) may be reduced to a nitrogen atom. More particularly, one or more of the N-oxide groups in a compound of formula (I) wherein Q1 represents a nitrogen atom in its oxidised form and R2 and/or R3 represents a heteroaryl group containing one or more nitrogen ring atoms in its oxidised form, may be reduced to a nitrogen atom. The reduction of an N-oxide group may be carried out by reaction with diphosphorus tetraiodide in an inert solvent, such as dichloromethane, preferably at or near room temperature, or by reaction with a chlorotrialkylsilane, preferably chlorotrimethylsilane, in the presence of zinc and an alkali metal iodide, e.g. potassium iodide, in an inert solvent, e.g. acetonitrile, at a temperature between about 0xc2x0 C. and about room temperature, preferably below room temperature.
According to a further example of the interconversion process, compounds of the invention containing hydroxy moieties may be converted to esters by the application or adaptation of known methods of esterification, for example, by reaction with an acid chloride (prepared by treatment of the appropriate acid with thionyl chloride or oxalyl chloride), preferably in the presence of a base, for example a tertiary amine, e.g. triethylamine. Alternatively, compounds of the invention containing hydroxy moieties may be reacted with the appropriate acid in the presence of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, and triphenylphosphine., preferably in a dry ethereal solvent, e.g. diethyl ether or tetrahydrofuran, preferably at or near room temperature.
As another example of the interconversion process, compounds of the invention containing hydroxy moieties may be prepared by hydrolysis of corresponding esters of the invention. The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide or carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50xc2x0 C. to about 80xc2x0 C.
As another example of the interconversion process, compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by a formyl group may be prepared by oxidising the corresponding compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by a hydroxymethyl group for example with oxalyl chloride and dimethyl sulphoxide, in a solvent such as dichloromethane, and preferably at a temperature lower than about xe2x88x9265xc2x0 C., or, preferably, by reaction with a complex of sulphur trioxide with an amine such as pyridine, preferably in the presence of an amine such as triethylamine, preferably at about room temperature.
As another example of the interconversion process, compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by an amino group may be prepared by reducing the corresponding compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by a nitro group, preferably with iron in acidic conditions, such as in acetic acid, preferably at or above room temperature, more especially at the reflux temperature. Alternatively the reduction may be carried out by reaction with hydrazine hydrate in the presence of ferric chloride and activated carbon, conveniently in a solvent such as methanol, at temperatures from about 25xc2x0 C. to about 80xc2x0 C.
As another example of the interconversion process, compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by an acylamino or aroylamino group may be prepared from compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by an amino group, preferably by means of reaction with the appropriate acid halide or acid anhydride in the presence of a tertiary base, such as triethylamine, optionally in an inert solvent, and preferably at a temperature from about 0xc2x0 C. to reflux.
As another example of the interconversion process, compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by a carboxamido group may be prepared from compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by a cyano group, by means of reaction with hydrogen peroxide and potassium carbonate in dimethyl sulphoxide.
As another example of the interconversion process, compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by a cyano group may be prepared from compounds of formula (I) wherein R3 represents a group containing R6 which is substituted by a bromine atom, by means of reaction with zinc cyanide in the presence of tetrakis(triphenylphosphine) palladium(0) in an inert solvent, such as dimethylformamide, at a temperature at about 100xc2x0 C.
As another example of the interconversion process, compounds of formula (I) wherein R1 is substituted by fluorine on a carbon atom thereof alpha to the attachment of R1 to Z1 as sulphur, may be prepared by reacting xenon difluoride with corresponding compound of formula (I) wherein said alpha-carbon atoms carry hydrogen atoms instead of said fluorine atoms. The reaction is conveniently carried out in a solvent, such as dichloromethane, in the presence of a molecular sieve, and in an inert atmosphere, at a low temperature, such as at about 0xc2x0 C.
As another example of the interconversion process, compounds of formula (I) wherein R1 is a difluoromethyl group and Z1 is an oxygen or sulphur atom, may be prepared by reacting a compound of formula (I) wherein R1 is a hydrogen atom and Z1 is an oxygen or sulphur atom, with HCBrF2 in the presence of a strong base in an inert solvent.
As another example, compounds of formula (I) wherein R3 represents a group containing R6 which is a heteroaryl group containing one or more nitrogen ring atoms but carrying no halogen substituents may be prepared by the reduction of the corresponding compounds of formula (I) wherein R3 represents a group containing R6 which does carry one or more halo, such as chloro, substituents, for example by means of ammonium formate in the presence of a palladium catalyst.
As another example, compounds of formula (I) wherein the moiety R3 contains a cis alkenyl group may be prepared by the action of ultraviolet radiation upon the trans-isomer.
As another example of the interconversion process, compounds of formula (l) wherein R3 contains a cis xe2x80x94Nxe2x95x90Nxe2x80x94 linkage may be prepared by the action of ultraviolet radiation upon their trans-isomers.
As another example of the interconversion process, compounds of formula (I) containing sulphoxide linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0xc2x0 C. and room temperature. This latter method is preferred for compounds containing an acid-labile group.
As another example of the interconversion process, compounds of formula (I) containing sulphone linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 or sulphoxide linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
As another example of the interconversion process, compounds of formula (I) wherein R3 represents a group containing a xe2x80x94CSCH2xe2x80x94 linkage may be prepared from compounds of formula (I) wherein R3 represents a group containing a xe2x80x94COCH2xe2x80x94 linkage by reaction with phosphorus pentasulphide or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide, preferably in a solvent such as pyridine or toluene, and preferably at a temperature from 0xc2x0 C. to the reflux temperature.
As another example of the interconversion process, compounds of formula (I) containing a hydroxymethyl group may be prepared by the reduction of the corresponding compounds of formula (I) containing an aryloxycarbonyl or, particularly, alkoxycarbonyl group, preferably by means of reaction with an alkali metal borohydride, preferably in an inert solvent, e.g. tetrahydrofuran, and preferably at or near room temperature.
As another example of the interconversion process, compounds of formula (Ib) in which R2 is hydrogen and A1 is a direct bond may be prepared by heating compounds of formula (Ib) in which the group R2 is a butyloxycarbonyl group and A1 is a direct bond.
According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from water.
The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
Intermediates of formula (II, T1xe2x80x94C(xe2x95x90O)X6) wherein T1 is as hereinbefore defined and X6 represents an O-benzotriazol-1-yl group may be prepared by reaction of compounds of formula (1):
T1xe2x80x94CO2Hxe2x80x83xe2x80x83(1)
wherein T1 is as hereinbefore defined, with O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2,-bis(tetramethylene)uronium tetrafluoroborate in an inert solvent, for example dichloromethane, at a temperature at about ambient temperature.
Intermediates of formula (II, T1xe2x80x94C(xe2x95x90O)X6) wherein T1 is as hereinbefore defined and X6 represents an azido group may be prepared from compounds of formula (1) wherein T1 is as hereinbefore defined by the application or adaptation of known methods for the preparation of acid azides from carboxylic acids. For example, the reaction may be carried out by means of diphenylphosphoryl azide in the presence of triethylamine in dimethylformamide.
Intermediates of formula (II, T1xe2x80x94C(xe2x95x90O)X6) wherein T1 is as hereinbefore defined and X6 represents a halogen atom may be prepared from compounds of the general formula (1) wherein T1 is as hereinbefore defined, by the application or adaptation of known methods for the preparation of acid halides from carboxylic acids. For example, when X6 represents a chlorine atom, the reaction may be carried out by means of thionyl chloride or, preferably, oxalyl chloride, optionally in the presence of a small amount of dimethylformamide.
Compounds of formula (1, T1xe2x80x94CO2H), wherein T1 is as hereinbefore defined may be prepared by hydrolysis of compounds of formula (IV, T1xe2x80x94CO2R49) wherein T1 and R49 are as hereinbefore defined. The hydrolysis may for example be carried out by reaction with a base, such as an alkali metal hydroxide, e.g. sodium or lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of water, in an alcohol such as methanol and at a temperature from about ambient to about reflux, followed by reaction with an aqueous acid such as dilute hydrochloric acid.
Intermediates of the general formula (III, R6NHR48) wherein R6 is as hereinbefore described, including N-oxides of heteroaryl groups, and R48 represents an alkanoyl group, e.g. acetyl group may be prepared for example, by the application or adaptation of known methods for the acylation or aromatic amines.
Intermediates of formula (IV) represented by the formula (2): 
wherein 
R53 represents CO2R49 (in which R49 is as hereinbefore defined), and R1, A1, Q1 and Z1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be prepared by reaction of compounds of formula (3): 
wherein R1, R2, A1, Q1 and Z1 are as hereinbefore described (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), and R53 represents xe2x80x94CO2R49 (in which R49 is as hereinbefore defined), with sodium hypochiorite in the presence of an aqueous acid such as dilute hydrochloric acid, in an alcohol, such as methanol, and at a temperature at about ambient temperature, followed by treatment of the resultant chloroimine with an alkali metal carbonate, such as sodium carbonate, at a temperature of about reflux temperature.
Intermediates of formula (VIII) represented by the formula (2), wherein 
represents 
R53 represents xe2x80x94C(xe2x95x90O)xe2x80x94R8 (in which R8 is optionally substituted alkyl), and R1, R2 and A1 are as hereinbefore defined, Q1 is CH and Z1 is an oxygen atom (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarly prepared from compounds of formula (3) wherein R1, R2 and A1 are as hereinbefore defined, R53 is a group xe2x80x94C(xe2x95x90O)xe2x80x94R8 (in which R8 is optionally substituted alkyl), Q1 is a CH linkage and Z1 is an oxygen atom (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl).
Intermediates of formula (X) represented by the formula (2), wherein 
represents 
R53 represents xe2x80x94C(xe2x95x90O)xe2x80x94R10 (in which R10 is a group xe2x80x94(CH2)pR6 where R6 and n are as hereinbefore defined); R1, R2 and A1 are as hereinbefore defined; Q1 is CH and Z1 is an oxygen atom (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarly prepared from compounds of formula (3) wherein R1, R2 and A1 are as hereinbefore defined, R53 is a group xe2x80x94C(xe2x95x90O)xe2x80x94R10 (in which R10 is a group xe2x80x94(CH2)pR6 in which R6 and n are as hereinbefore defined), Q1 is a CH linkage and Z1 is an oxygen atom (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl).
Intermediates of formula (XVIII) represented by the formula (2), wherein 
represents 
R53 represents a halogen atom, Q1 is a CH linkage, Z1 is an oxygen atom and R1, R2 and A1 are as hereinbefore defined, (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarly prepared from compounds of formula (3) wherein 
R53 is a halogen atom, Q1 is a CH linkage, Z1 is an oxygen atom and R1, R2 and A1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl cycloalkyl, aryl, or heteroaryl).
Compounds of formula (18) represented by the formula (2), wherein R53 is a nitro group and 
R1, R2, A1, Q1 and Z1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarly prepared from compounds of formula (3) wherein R53 is a nitro group and R1, R2, A1, Q1 and Z1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl).
Compounds of formula (19), represented by the formula (2), wherein R53 is a methyl group and 
R1, R2, A1, Q1 and Z1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarly prepared from compounds of formula (3) wherein R53 is a methyl group and R1, R2, A1, Q1 and Z1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl).
Compounds of formula (3), wherein R1, R2, R53, A1, Q1 and Z1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be prepared by reaction of compounds of formula (4): 
wherein R1, R53, Q1 and Z1 are as hereinbefore defined, with compounds of formula R2A1Cxe2x89xa1N, wherein R2 and A1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), in the presence of an acid catalyst, such as 4-toluenesulphonic acid, at a temperature up to about 180xc2x0 C.
Intermediates of formula (XXXXV) wherein R1, R2, R3, A1, Q1 and Z1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarly prepared by reaction of compounds of formula (4) wherein R1, Q1 and Z1 are as hereinbefore defined and R53 is a group xe2x80x94R3, with compounds of formula R2A1 Cxe2x89xa1N, wherein R2 and A1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), in the presence of an acid catalyst, such as 4-toluenesulphonic acid, at a temperature up to about 180xc2x0 C.
Compounds of formula (4) wherein R1 is as hereinbefore defined, R53 represents a group xe2x80x94CO2R49 in which R49 is as hereinbefore defined, Z1 represents an oxygen atom and Q1 represents a nitrogen atom, may be prepared by reaction of compounds of formula (5): 
wherein R1 and R49 are as hereinbefore defined, with ammonium hydroxide in the presence of sulphur dioxide according to the procedure of H. King, J. Chem. Soc, 1946, page 523.
Compounds of formula (4) wherein R1 and R53 are as hereinbefore defined, Z1 represents an oxygen atom or a direct bond and Q1 represents a CH or a CF linkage, may be prepared by reduction of compounds of formula (6): 
wherein R1 and R53 are as hereinbefore defined, Z1 represents an oxygen atom or a direct bond and Q1 represents a CH or a CF linkage. The reduction may conveniently be carried out using hydrogen in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. Alternatively the reduction may be carried out ammonium chloride and iron, in an aqueous/organic solvent mixture, for example aqueous methanol, at a temperature at about reflux.
Compounds of formula (6), wherein R1 and R53 are as hereinbefore defined, Z1 represents an oxygen atom or a direct bond and Q1 represents a CH or a CF linkage, may be prepared by nitration of compounds of formula (7): 
wherein R1 and R53 are as hereinbefore defined, Z1 represents an oxygen atom or a direct bond and Q1 represents a CH or a CF linkage, with fuming nitric acid at a temperature from about ambient temperature to about 60xc2x0 C., and separation of the required nitro-isomer (6).
Compounds of formula (6), wherein R1 is C 1-4alkyl, R53 is a bromine atom, Q1 represents a CH linkage and Z1 represents an oxygen atom, may be prepared by bromination of the appropriate 2-(C1-4alkoxy)nitrobenzene according to the procedure of S. Kajigaeshi et. al. J. C. S. Perkin Trans.I, 1990, page 897.
Compounds of formula (6), wherein R1 is C1-4alkyl, R53 is an iodine atom, Q1 represents a CH linkage and Z1 represents an oxygen atom, may be prepared by thallation of the appropriate 2-(C1-4alkoxy)-nitrobenzene with thallium trifluoroacetate in trifluoroacetic acid followed by iodination with aqueous potassium iodide according to the procedure of A. Mckillop et. al. Tetrahedron. Letters, 1969, page 2427.
Compounds of formula (4), wherein R1 is as hereinbefore defined and R53 is a group xe2x80x94SO2NR21R22 in which R21 and R22 are as hereinbefore described, Q1 is a CH linkage and Z1 is an oxygen atom, may be prepared from reaction of 3-acetamido-4-methoxybenzene sulphonyl chloride (prepared according to the procedure of B. M. Culbertson, J. Chem. Soc., 1968, page 992) with amines of formula R21R22NH wherein R21 and R22 are as hereinbefore described and subsequent treatment with sodium hydroxide.
Compounds of formula (7), wherein R1 is as hereinbefore defined, R53 represents xe2x80x94CO2R49 (in which R49 is as hereinbefore defined), Z1 represents an oxygen atom and Q1 represents a CF linkage may be prepared by reaction of compounds of formula (8): 
wherein R1 is as hereinbefore defined, with the appropriate C1-5alkyl alcohol, in the presence of hydrogen chloride at a temperature up to about reflux.
Compounds of formula (8), wherein R1 is as hereinbefore defined, may be prepared by reaction of 4-hydroxy-2-fluorobenzonitrile with compounds of the formula (9):
R1X12xe2x80x83xe2x80x83(9)
wherein R1 is as hereinbefore described and X12 is a bromine or chlorine atom, or a triflate group. The reaction may be carried out in the presence of an alkali metal carbonate, such as potassium carbonate, in an inert solvent such as dimethylformamide, and at a temperature from about room temperature to about 80xc2x0 C.
Intermediates of formula (2), wherein 
R53 represents xe2x80x94CO2R49 (in which R49 is as hereinbefore defined), A1 is a direct bond, R2 is an alkoxy group, and R1, Q1 and Z1 are as hereinbefore defined, may be prepared by reaction of compounds of formula (10): 
wherein R1, R49, Q1 and Z1 are as hereinbefore described, with compounds of formula (XXXXVIII), wherein R49 is as hereinbefore defined. The reaction is carried out in acetic acid at a temperature up to about reflux temperature.
Intermediates of formula (2), wherein represents 
R53 represents xe2x80x94CO2R49 (in which R49 is as hereinbefore defined), and R1, A1, Q1 and Z1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be prepared by reaction of compounds of formula (10), wherein R1, R49, Q1 and Z1 are as hereinbefore described, with compounds of formula (XXXXVII, R2A1C(xe2x95x90O)X10), wherein R2 and A1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), and X10 represents a hydroxy group or a halogen atom, preferably a chlorine atom. When X10 represents a hydroxy group the reaction is preferably carried out in the hydrochloric acid at a temperature at about 125xc2x0 C. When X10 represents a chlorine atom the reaction is preferably carried out in an inert solvent, such as dichloromethane, optionally in the presence of triethylamine and at a temperature from about 0xc2x0 C. to about ambient temperature, followed by reaction of the product with acetic acid at a temperature at about reflux.
Compounds of formula (10), wherein R1, R49 and Z1 are as hereinbefore defined and Q1 represents a CH linkage, may be prepared by reduction of compounds of formula (11): 
wherein R1, R49 and Z1 are as hereinbefore described. The reduction may be carried out using hydrogen in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
Compounds of formula (11) wherein R1, R49 and Z1 are as hereinbefore described may be prepared by conversion of the carboxy group in compounds of formula (12): 
wherein R1, R49 and Z1 are as hereinbefore described, into an amino group. The process involves initial reaction with thionyl chloride, in an inert solvent such as toluene, in the presence of dimethylformamide and at a temperature at about reflux, to form the corresponding acid chloride. The acid chloride is then reacted with a sodium azide in aqueous acetone at a temperature from about 0xc2x0 C. to about ambient temperature to form the corresponding acid azide, which is heated in an aqueous alcohol, such as t-butanol, at a temperature at about reflux.
Compounds of formula (12) wherein R1, R49 and Z1 are as hereinbefore described may be prepared by esterification of the corresponding phthalic acid of formula (13): 
wherein R1 and Z1 are as hereinbefore described with the appropriate C1-5alkyl alcohol.
Compounds of formula (13) wherein R1 and Z1 are as hereinbefore described may be prepared by nitration of the corresponding phthalic acid of formula (14): 
wherein R1 and Z1 are as hereinbefore described, with fuming nitric acid at a temperature from about ambient temperature to about 60xc2x0 C.
Intermediates of formula (2), wherein 
(in which R5 represents a C1-4straight- or branched-chain alkyl, an arylC1-4alkyl or a heteroarylC1-4alkyl group), R53 represents xe2x80x94CO2R49 (in which R49 is as hereinbefore defined), and R1, R2, A1, Q1 and Z1 are as hereinbefore defined, may be prepared by reaction of compounds of formula (2), wherein represents 
R53 represents xe2x80x94CO2R49 (in which R49 is as hereinbefore defined), and R1, R2, A1, Q1 and Z1 are as hereinbefore defined, with a C1-4straight- or branched-chain alkyl halide or a arylC1-4alkyl halide or a heteroarylC1-4alkyl halide respectively. The alkylation may for example be carried out in the presence of a base, such as an alkali metal hydride, e.g. sodium hydride, in dimethylformamide at a temperature from about 0xc2x0 C. to about ambient temperature.
Intermediates of formula (IV) or (XXXIII) represented by formula (15): 
wherein R1, R2, A1, and Z1 are as hereinbefore defined, R53 represents xe2x80x94CO2R49 (in which R49 is as hereinbefore defined) or OH, and Q is CH or N, may be prepared for example by the application or adaptation of known methods for the substitution of the imino (NH) group in indoles or indazines of general formula (16): 
wherein R1 and Z1 are as defined previously, R53 represents xe2x80x94CO2R49 (in which R49 is as hereinbefore defined), and Q is CH or N.
Intermediates of formula (16) wherein R1 and Z1 are as defined previously, R53 represents CO2R49 (in which R49 is as hereinbefore defined) and Q is N may be prepared from compounds of general formula (17), wherein R1 and Z1 are as hereinbefore defined, as shown in Scheme (I): 
Scheme (I)
Reaction Conditions:
(i) treatment with boron tribromide in an inert solvent, such as dichloromethane, at a temperature from about 0xc2x0 C. to about reflux temperature.
(ii) treatment with N-phenyltrifluoromethane sulphonimide in the presence of a suitable base such as sodium hydride in an inert solvent, such as tetrahydrofuran, at a temperature at about 50xc2x0 C.
(iii) treatment with carbon monoxide in the presence of palladium acetate, diphenylphbsphine ferrocene, triethylamine and methanol.
(iv) treatment with a suitable base, e.g. an alkali metal carbonate, such as potassium carbonate, in a mixture of an alcohol, such as methanol, and water at a temperature up to about reflux temperature.
(v) treatment with the appropriate alcohol R49xe2x80x94OH in the presence of hydrogen chloride at room temperature.
Compounds of general formula (17), wherein R1 is methyl and Z1 is a direct bond may be prepared by treatment of 2-fluoro-4-methoxyacetophenone with hydrazine at a temperature up to about reflux temperature.
Compounds of formula (16) wherein R1 and Z1 are as defined previously, R53 represents OH and Q is N may be prepared from compounds of general formula (17), wherein R1 and Z1 are as hereinbefore defined, as shown in the first step of Scheme (I).
Intermediates of formula (VI), wherein T1 and R6 are as hereinbefore defined, may be prepared by reaction of compounds of formula (XXVI) wherein T1 is as hereinbefore defined with compounds of general formula (V), wherein R6 is as hereinbefore described, in the presence of a strong base such as lithium diisopropylamine, in an inert solvent, for example an ether such as tetrahydrofuran, preferably at a temperature from xe2x88x9265xc2x0 C. to 0xc2x0 C.
Intermediates of formula (VIII), wherein T1 is as hereinbefore defined, and R8 is hydrogen [i.e. T1xe2x80x94C(xe2x95x90O)H, compounds of formula (XXVI)] may be prepared by oxidation of compounds of formula (XXIX) with manganese dioxide in an inert solvent, such as dichloromethane or toluene (or a mixture of both), and at a temperature from about room temperature to about 85xc2x0 C.
Intermediates of formula (XIV), wherein T1, R10, R11 and R12 are as hereinbefore defined, may be prepared by reaction of compounds of formula (X) wherein T1 and R10 are as hereinbefore defined, with an organometallic reagent R11 (R12)CHM [where M is a metal atom, for example a lithium atom] in a solvent such as an ether (e.g. tetrahydrofuran) at a low temperature, e.g. about xe2x88x9278xc2x0 C. to ambient temperature. Reagents R11 (R12)CHM are either known compounds or may be prepared, preferably in situ during the above process, by reaction of a compound AlkCH2M or [Alk]2NM [where Alk is an alkyl group such as n-propyl or i-propyl] with a compound R11CH2R12 using the just mentioned conditions. Intermediates of formula (XV, T1xe2x80x94C(R8)(OH)CH(R9)(CH2)pR6), wherein T1, R6, R8 and R9 are as hereinbefore defined, may be similarly prepared by reaction of compounds of formula (VIII) wherein T1 and R8 are as hereinbefore defined, with an organometallic reagent R6(CH2)p(R9)CHM [where M is a metal atom, for example a lithium atom].
Intermediates of formula (XVI, T1xe2x80x94B(OH)2), wherein T1 is as hereinbefore defined, may be prepared by reaction of compounds of formula (XVIII), wherein T1 is as hereinbefore defined, with n-butyl lithium, in an inert solvent such as tetrahydrofuran, at a temperature about xe2x88x9278xc2x0 C., followed by reaction with a trialkylborate, such as triethyl borate, and subsequent hydrolysis with a dilute mineral acid such as hydrochloric acid.
Intermediates of formula (XX, T1xe2x80x94NH2), wherein T1 is as hereinbefore defined, may be prepared by hydrogenation of compounds of formula (18):
T1xe2x80x94NO2xe2x80x83xe2x80x83(18)
wherein T1 is as hereinbefore defined. The hydrogenation may be carried out using hydrogen in the presence of a suitable metal catalyst, e.g. palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
Intermediates of formula (XXII, T1xe2x80x94C(xe2x95x90NOH)CH3), wherein T1 is as hereinbefore defined, may be prepared by reaction of compounds of formula (VIII) wherein T1 is as hereinbefore described and R8 is methyl, with hydroxylamine hydrochloride in the presence of pyridine, in an inert solvent, such as dichloromethane, at a temperature at about room temperature.
Intermediates of formula (XXV, T1xe2x80x94CH2CH(OH)R6), wherein T1 and R6 are as hereinbefore defined, may be prepared by reaction of compounds of formula (19):
T1xe2x80x94CH3xe2x80x83xe2x80x83(19)
wherein T1 is as hereinbefore described, with a strong base such as lithium diisopropylamide, in an inert solvent, such as tetrahydrofuran at a temperature at about xe2x88x9278xc2x0 C. followed by reaction of with compounds of formula (XXXII, R6CHO) wherein R6 is as hereinbefore described.
Intermediates of formula (XXVII, T1xe2x80x94CH2X7), wherein T1 is as hereinbefore described and X7 is a bromine atom, may be prepared by bromination of compounds of formula (19), wherein T1 is as hereinbefore described, with N-bromosuccinimide, optionally in the presence of a catalyst, such as benzoyl peroxide, in an inert solvent such as dichloromethane and at a temperature at about room temperature.
Alternatively intermediates of formula (XXVII, T1xe2x80x94CH2X7), wherein T1 is as hereinbefore described and X7 is a bromine atom, may be prepared by reaction of compounds of formula (XXIX, T1CH2OH), wherein T1 is as hereinbefore described, with N-bromosuccinimide, optionally in the presence of a catalyst, such as benzoyl peroxide, in an inert solvent such as dichloromethane and at a temperature at about room temperature.
Intermediates of formula (XXIX, T1xe2x80x94CH2OH), wherein T1 is as hereinbefore described may be prepared by reduction of compounds of formula (IV, T1xe2x80x94CO2R49) wherein T1 and R49 are as hereinbefore described. The reduction may conveniently be carried out with diisobutylaluminium hydride in an inert solvent, such as tetrahydrofuran, at a temperature from about xe2x88x9278xc2x0 C. to about room temperature. The reduction may also be carried out with lithium aluminium hydride in an inert solvent, such as an ether, for example diethyl ether, at a temperature from about room temperature to about reflux. Intermediates of formula (XXXI) wherein T1 is as hereinbefore defined may be prepared from compounds of the general formula (20):
T1xe2x80x94CHF2xe2x80x83xe2x80x83(20)
wherein T1 is as hereinbefore defined, by reaction with bromine in carbon tetrachloride and ultraviolet radiation, at a temperature from about ambient to about reflux.
Compounds of formula (20) wherein T1 is as hereinbefore defined may be prepared by the action of sulphur tetrafluoride and hydrofluoric acid on compounds of formula (XXVI) wherein T1 is as hereinbefore defined, optionally in the presence of pyridine, at a temperature from about room temperature to about 125xc2x0 C., or alternatively by the action of diethylaminosulphur trifluoride, preferably in an inert solvent, such as dichloromethane, preferably at a temperature from about 0xc2x0 C. to about room temperature.
Intermediates of formula (XXXVII, T1xe2x80x94N2+BF4xe2x88x92), wherein T1 is as hereinbefore defined may be prepared by diazotisation of compounds of formula (XX) with sodium nitrite in the presence of hydrochloric acid, followed by treatment with sodium tetrafluoroborate.
Intermediates of formula (XXXX, T1-SO2Cl), wherein T1 is as hereinbefore defined may be prepared by reaction of compounds of formula (XVIII, T1-X7), wherein T1 is as hereinbefore defined and X7 is a bromine atom with butyllithium in tetrahydrofuran at a temperature at about xe2x88x9270xc2x0 C. followed by treatment with sulphur dioxide at about the same temperature and subsequent reaction of the resulting lithium sulphinate salt with sulphuryl chloride in an inert solvent such as dichloromethane at a temperature at about 0xc2x0 C.
Intermediates of formula (XXXXII, T1xe2x80x94C(xe2x95x90O)CO2H), wherein T1 is as hereinbefore defined may be prepared by the oxidation of compounds of formula (VIII, T1xe2x80x94C(xe2x95x90O)R8) wherein T1 is as hereinbefore described and R8 is methyl, by reaction with selenium dioxide in the presence of pyridine, using mild conditions, e.g. in a solvent such as ethanol, at or below room temperature.
Intermediates of the general formula (XXXXIII) wherein T1 is as hereinbefore defined may be prepared by treatment of compounds of formula (XX) wherein T1 is as hereinbefore defined with the phosgene equivalent (ClC(xe2x95x90O)OCCl3) in an inert solvent such as dioxan at a temperature at about 60xc2x0 C.
Intermediates of formulae (XXXXIX), (L) and (LII) wherein R1, R3, 
Q1 and Z1 are as hereinbefore described, may be prepared by the application or adaptation of methods for the reactions of o-arylenediamines described in Comprehensive Heterocyclic Chemistry, page 470.
Intermediates of formula (LIV, T1xe2x80x94C(CN)[(CH2)2CO2R52]2), wherein T1 is as hereinbefore described, may be prepared by reaction of compounds of formula (21):
T1xe2x80x94CH2CNxe2x80x83xe2x80x83(21)
wherein T1 is as hereinbefore described, with methyl (or ethyl) acrylate in methanol, in the presence of a suitable catalyst, such as Triton-B, and at reflux temperature.
Compounds of formula (21), wherein T1 is as hereinbefore described, may be prepared by reaction of compounds of formula (XXVII), wherein T1 is as hereinbefore described and X7 represents a chlorine atom, with sodium cyanide in dimethylformamide. Intermediates of the general formula (LV, T1xe2x80x94CHxe2x95x90CHxe2x80x94CO2H) wherein T1 is as hereinbefore described may be prepared by reaction of compounds of formula (XXVI, T1xe2x80x94CHO) with malonic acid in the presence of piperidine in a solvent such as pyridine at a temperature up to about reflux.
Intermediates of the general formula (LVII), wherein T1 is as hereinbefore described may be prepared by reaction of compounds of formula (22):
T1xe2x80x94CHxe2x95x90CHCO2R49xe2x80x83xe2x80x83(22)
wherein T1 and R49 are as hereinbefore described, with an nitromethane in the presence of tetramethylguanidine at a temperature at about 65xc2x0 C.
Compounds of formula (22), wherein T1 and R49 are as hereinbefore described may be prepared by reaction of compounds of formula (XXVI) with a carboalkoxymethylene triphenylphosphorane, e.g. carbomethoxymethylene triphenylphosphorane, in an inert solvent, such as toluene, and at a temperature from about room temperature to about 80xc2x0 C.
Intermediates of formula (LVIII), wherein T1 is as hereinbefore described, may be prepared from compounds of formula (23):
T1xe2x80x94CH(NHCO2Me)CH2CHxe2x95x90CH2xe2x80x83xe2x80x83(23)
wherein T1 is as hereinbefore described, following hydroboration of the double bond with for example diisoamylborane in tetrahydrofuran at 0xc2x0 C. and subsequent treatment with sodium hydroxide and hydrogen peroxide at 0xc2x0 C.
Compounds of formula (23), wherein T1 is as hereinbefore described, may be prepared by reaction of compounds of formula (24):
T1xe2x80x94CH(CO2H)CH2CHxe2x95x90CH2xe2x80x83xe2x80x83(24)
wherein T1 is as hereinbefore described, with thionyl chloride, at room temperature, followed by reaction of the resulting acid chloride with sodium azide in acetone at 0xc2x0 C. to room temperature then thermolysis by refluxing in an inert solvent such as benzene to furnish the isocyanate which may be converted to the required urethane by refluxing in methanol.
Compounds of formula (24, T1xe2x80x94CH(CO2H)CH2CHxe2x95x90CH2), wherein T1 is as hereinbefore described, may be prepared by alkylation of the acid dianion (obtained following treatment with two equivalents of lithium diisopropylamine in tetrahydrofuran) derived from compounds of formula (25):
T1xe2x80x94CH2CO2Hxe2x80x83xe2x80x83(25)
wherein T1 is as hereinbefore described, with allyl bromide.
Intermediates of formula (Iz) wherein T1 is as hereinbefore described and the moiety R3 represents a 
group in which R52 is a methyl or ethyl group, may be prepared from compounds of formula (XXVI) by reaction with hydroxylamine hydrochloride in the presence of pyridine, followed by treatment of the so formed oxime with N-chlorosuccinimide and pyridine in an inert solvent, such as dichloromethane, and subsequent reaction of the chloroamidoxime with methyl or ethyl acrylate in the presence of triethylamine.
Intermediates of formula (LIX), wherein R1, R2, A1, Q1 and Z1 are as hereinbefore defined, R3 represents a xe2x80x94Oxe2x80x94CH2xe2x80x94R6 group where R6 is as hereinbefore defined, and 
is a suitable protecting group, for example a 2-trimethylsilanyl-ethoxymethyl group, may be prepared by reaction of compounds of formula (26): 
wherein R1, R2, A1, Q1 and Z1 are as hereinbefore defined, and 
is a suitable protecting group, for example a 2-trimethylsilanyl-ethoxymethyl group, with compounds of formula (27):
R6CH2OHxe2x80x83xe2x80x83(27)
wherein R6 is as hereinbefore defined, in the presence of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, and triphenylphosphine, preferably in a dry ethereal solvent, e.g. diethyl ether or tetrahydrofuran, preferably at or near room temperature.
Compounds of formula (26) wherein R1, R2, A1, Q1 and Z1 are as hereinbefore defined, and 
is a suitable protecting group, for example a 2-trimethylsilanyl-ethoxymethyl group, may be prepared by reaction of compounds of formula (28): 
wherein R1, R2, A1, Q1 and Z1 are as hereinbefore defined, and 
is a suitable protecting group, for example a 2-trimethylsilanyl-ethoxymethyl group, with m-chloroperbenzoic acid in an inert solvent such dichloromethane and at a temperature from about 0xc2x0 C. to about room temperature followed by treatment with sodium hydrogen carbonate.
Intermediates of formula (XXXIII), wherein T1 is as hereinbefore defined, may be similarly prepared by reaction of compounds of formula (XXVI), wherein T1 is as hereinbefore defined, with m-chloroperbenzoic acid.
Compounds of formula (28) wherein R1, R2, A1, Q1 and Z1 are as hereinbefore defined, and 
is a 2-trimethylsilanyl-ethoxymethyl group, may be prepared by reaction of compounds of formula (2), wherein 
R53 represents a formyl group, and R1, R2, A1, Q1 and Z1 are as hereinbefore defined, with 2-(trimethylsilyl)ethoxymethyl chloride in the presence of sodium hydride, in an inert solvent such as dimethylformamide, and at a temperature at about room temperature.
Compounds of formula (XXXIV) wherein R6 is as hereinbefore defined and X8 is hydroxy may be prepared by reduction of compounds of formula (XXXII) wherein R6 is as hereinbefore defined. The reduction may conveniently be carried out with sodium borohydride in an alcohol such as ethanol at a temperature at about room temperature.
Compounds of formula (XXXII) wherein R6 is heteroaryl, such as a substituted pyridyl, for example 3,5-dimethylpyridyl, may be prepared by reaction of compounds of formula (29):
R6Brxe2x80x83xe2x80x83(29)
wherein R6 is heteroaryl, such as a substituted pyridyl, for example 3,5-dimethylpyridyl, with butyl lithium in an inert solvent, such as diethyl ether, at xe2x88x9278xc2x0 C., and subsequent treatment of the resulting anion with dimethylformamide.
Compounds of formula (29) wherein R6 is 3,5-dimethylpyridyl, may be prepared by reaction of 4-nitro-3,5-dimethylpyridine-N-oxide with phosphorous tribromide in a similar manner to the procedures described in J.Chem.Soc., 1956, page 771.
Intermediates of formula (IV) represented by formula (30): 
wherein R1, R2, A1, and Z1 are as hereinbefore defined, R53 is CO2R49 (in which R49 is as hereinbefore defined), may be prepared for example by reaction of compounds of formula (4), wherein R1 and Z1 are as hereinbefore defined, R53 is CO2R49 (in which R49 is as hereinbefore defined) and Q is CH, with compounds of formula (31):
R2A1xe2x80x94CHxe2x95x90CHxe2x80x94CHOxe2x80x83xe2x80x83(31)
wherein R2 and A1 are as hereinbefore defined, in the presence of p-chloranil in a alcohol, such as butanol, and at a temperature at about reflux temperature.
Intermediates of formula (IV) represented by formula (32): 
wherein R1 is hydrogen, R2 is alkyl, aryl or heteroaryl, R53 is CO2R49 (in which R49 is as hereinbefore defined), Z1 is a direct bond, and A1 is xe2x80x94CH2xe2x80x94 or xe2x80x94CH(CH3)xe2x80x94, may be prepared for example by reaction of compounds of formula (33): 
wherein R49 is as hereinbefore defined, R2 is alkyl, aryl or heteroaryl, and R54 is hydrogen or methyl, with palladium acetate in the presence of triethylamine in an inert solvent such as acetonitrile, sealed in a bomb, and at a temperature up to about 110xc2x0 C.
Compounds of formula (33), wherein R2, R53 and A1 are as hereinbefore defined, may be prepared by reaction of compounds of formula (34):

wherein R53 is as hereinbefore defined with an allyl bromide of formula (35):
R2(R54)Cxe2x95x90CHxe2x80x94CHBrxe2x80x83xe2x80x83(35)
wherein R2 and R54 are as defined above, in the presence of lithium diisopropylamide in an inert solvent such as an ether, e.g. tetrahydrofuran, at a temperature from about xe2x88x9278xc2x0 C. to about room temperature.
Compounds of formula (34) may be prepared according to the method of Hill, Tetrahedron, 1990, 46, page 4587.
Intermediates of formula (IV) represented by formula (36): 
wherein R1, R2, A1, and Z1 are as hereinbefore defined, and R53 is CO2R49, may be prepared for example by reaction of compounds of formula (37): 
wherein R1, R49 and Z1 are as hereinbefore defined, with compounds of formula R2A1Cxe2x89xa1N, wherein R2 and A1 are as hereinbefore defined (with the proviso that when A1 is a direct bond then R2 is alkyl, cycloalkyl, aryl, or heteroaryl), in the presence of an acid catalyst, such as 4-toluenesulphonic acid, at a temperature up to about 180xc2x0 C.
Compounds of formula (37), wherein R1 and Z1 are as hereinbefore defined, may be prepared by reduction of compounds of formula (38): 
wherein R1, R49 and Z1 are as hereinbefore defined. The reduction may be carried out using hydrogen in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as ethyl acetate.
Compounds of formula (38), wherein R49 is as hereinbefore defined, R1 is methyl and Z1 is an oxygen atom, may be prepared by nitration of methyl 4-methoxysalicylate followed by separation of the required nitro-isomer. The nitration may be conveniently carried out using concentrated nitric acid in acetic acid at a temperature at about room temperature.
Intermediates of formula (IV) represented by formula (39): 
wherein R1 is alkyl, R2 is alkyl, aryl or heteroaryl, R53 is CO2R49 (in which R49 is as hereinbefore defined), Z1 is a direct bond, and A1 is as hereinbefore defined, may be prepared for example by reduction of compounds of formula (15), wherein R1 is alkyl, R2 is alkyl, aryl or heteroaryl, R53 is CO2R49 (in which R49 is as hereinbefore defined), Q is CH, Z1 is a direct bond, and A1 is as hereinbefore defined, using a solution of borane-tetrahydrofuran complex in tetrahydrofuran. The reaction may conveniently be carried out in trifluoroacetic acid at a temperature at about 0xc2x0 C.
Intermediates of formula (IV) represented by formula (40): 
wherein R1, R2, A1 and Z1 are as hereinbefore defined, and R53 is CO2R49 (in which R49 is as hereinbefore defined), may be prepared for example by reaction of compounds of formula (37), wherein R1, R49 and Z1 are as hereinbefore defined with compounds of formula (41):
R2A1CH(Cl)C(xe2x95x90O)Clxe2x80x83xe2x80x83(41)
wherein R1 and A1 are as hereinbefore defined, in an inert solvent such as dichloromethane, in the presence of a base, such as sodium hydrogen carbonate, and at a temperature from about 0xc2x0 C. to about room temperature, followed by heating the intermediate with potassium carbonate in dimethylformamide at 100xc2x0 C. and then reduction with borane-dimethylsulphide complex in tetrahydrofuran at room temperature.
Intermediates of formula (IV) represented by formula (41): 
wherein R1, R49 and Z1 are as hereinbefore defined, R2 is alkoxy, arylalkyloxy, heteroarylalkyloxy or hydroxy and A1 is methylene may be prepared for example by reaction of compounds of formula (42): 
wherein R1, R49 and Z1 are as hereinbefore defined, with with sodium hypochlorite in the presence of an aqueous acid such as dilute hydrochloric acid, in an alcohol, such as methanol, and at a temperature at about reflux temperature, followed by treatment of the resultant chloroimine with water or an alcohol of formula R2xe2x80x94OH where R2 is as defined immediately above, in the presence of an alkali metal carbonate, such as potassium carbonate, at a temperature at about reflux temperature Compounds of formula (42) wherein R1, R49 and Z1 are as hereinbefore defined, may be prepared by reaction of compounds of formula (4) wherein R1 and Z1 are as hereinbefore defined, R53 is CO2R49 (in which R49 is as hereinbefore defined) and Q1 is CH, with chlorocetonitrile in the presence of an acid catalyst, such as 4-toluenesulphonic acid, and at a temperature at about 180xc2x0 C.
Intermediates of formulae (II), (IV), (VI), (VIII), (X), (XIV), (XV), (XVI), (XVIII), (XX), (XXII), (XXIII), (XXV), (XXVI), (XXVII), (XXIX), (XXXI), (XXXIII), (XXXV), (XXXVII), (XXXX), (XXXXII), (XXXXIII), (XXXXV), (XXXXIX), (L), (LII), (LIV), (LV), (LVIII) and (LIX) are novel compounds and, as such, they and their processes described herein for their preparation constitute further features of the present invention.
The present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
In the nuclear magnetic resonance spectra (NMR) the chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances: s=singlet; d=doublet; t=triplet; m=multiplet; dd=doublet of doublets; b=broad.